Compound

ABSTRACT

The present invention involves tetrahydroisoquinoline compounds and their use in the inhibition and/or prevention of tumor growth.

FIELD OF INVENTION

The present invention relates to a compound.

In particular the present invention relates to a compound and to apharmaceutical composition comprising the compound. The presentinvention also relates to the use of the compound or composition intherapy applications.

BACKGROUND TO THE INVENTION

Evidence suggests that oestrogens are the major mitogens involved inpromoting the growth of tumours in endocrine-dependent tissues, such asthe breast and endometrium. Although plasma oestrogen concentrations aresimilar in women with or without breast cancer, breast tumour oestroneand oestradiol levels are significantly higher than in normal breasttissue or blood. In situ synthesis of oestrogen is thought to make animportant contribution to the high levels of oestrogens in tumours andtherefore inhibitors, in particular specific inhibitors, of oestrogenbiosynthesis are of potential value for the treatment ofendocrine-dependent tumours.

Over the past two decades, there has been considerable interest in thedevelopment of inhibitors of the aromatase pathway—which converts theandrogen precursor androstenedione to oestrone. However, there is nowevidence that the oestrone sulphatase (E1-STS) pathway, i.e. thehydrolysis of oestrone sulphate to oestrone (E1S to E1), and aromatase(i.e. conversion of androstenedione to oestrone) account for theproduction of oestrogens in breast tumours.

FIGS. 1 and 2 are schematic diagrams showing some of the enzymesinvolved in the in situ synthesis of oestrone from oestrone sulphate,oestradiol and androstenedione.

In FIG. 2, which schematically shows the origin of oestrogenic steroidsin postmenopausal women, “ER” denotes Oestrogen Receptor, “DHA-S”denotes Dehydroepiandrosterone-Sulphate, “Adiol” denotes Androstenediol,“E1-STS” denotes Oestrone Sulphatase, “DHA-STS” denotes DHA-sulphatase,“Adiol-STS” denotes Adiol Sulphatase, and “17B-HSD” denotes Oestradiol17B-hydroxysteroid dehydrogenase.

As can be seen, the main two enzymes that are involved in the peripheralsynthesis of oestrogens are the aromatase enzyme and the enzyme oestronesulphatase.

In short, the aromatase enzyme converts androstenedione, which issecreted in large amounts by the adrenal cortex, to oestrone. Recentreports have suggested that some flavones could inhibit aromataseactivity.

Much of the oestrone so formed, however, is converted to oestronesulphate (E1S) and there is now a considerable body of evidence showingthat E1S in plasma and tissue acts as a reservoir for the formation ofoestrone by the action of oestrone sulphatase.

In this regard, it is now believed that the oestrone sulphatase (E1-STS)pathway—i.e. the hydrolysis of oestrone sulphate to oestrone (E1S to E1)is a major source of oestrogen in breast tumours. This theory issupported by a modest reduction of plasma oestrogen concentration inpostmenopausal women with breast cancer treated by aromatase inhibitors,such as aminoglutethimide and 4-hydroxyandrostenedione and also by thefact that plasma E1S concentration in these aromatase inhibitor-treatedpatients remains relatively high. The long half-life of E1S in blood(10-12 h) compared with the unconjugated oestrogens (20 min) and highlevels of steroid sulphatase activity in liver and, normal and malignantbreast tissues, also lend support to this theory.

Thus, oestrogen formation in malignant breast and endometrial tissuesvia the sulphatase pathway makes a major contribution to the highconcentration of oestrogens which are present in these tumours.

PCT/GB92/01587 teaches novel steroid sulphatase inhibitors andpharmaceutical compositions containing them for use in the treatment ofoestrone dependent tumours, especially breast cancer. These steroidsulphatase inhibitors are sulphamate esters, such as N,N-dimethyloestrone-3-sulphamate and, preferably, oestrone-3-sulphamate (otherwiseknown as “EMATE”). EMATE has the following structure:

It is known that EMATE is a potent E1-STS inhibitor as it displays morethan 99% inhibition of E1-STS activity in intact MCF-7 cells at 0.1 nM.EMATE also inhibits the E1-STS enzyme in a time- andconcentration-dependent manner, indicating that it acts as an activesite-directed inactivator. Although EMATE was originally designed forthe inhibition of E1-STS, it also inhibits dehydroepiandrosteronesulphatase (DHA-STS), which is an enzyme that is believed to have apivotal role in regulating the biosynthesis of the oestrogenic steroidandrostenediol. Also, there is now evidence to suggest thatandrostenediol may be of even greater importance as a promoter of breasttumour growth. EMATE is also active in vivo as almost completeinhibition of rat liver E1-STS (99%) and DHA-STS (99%) activitiesresulted when it is administered either orally or subcutaneously. Inaddition, EMATE has been shown to have a memory enhancing effect inrats. Studies in mice have suggested an association between DHA-STSactivity and the regulation of part of the immune response. It isthought that this may also occur in humans. The bridging O-atom of thesulphamate moiety in EMATE is important for inhibitory activity. Thus,when the 3-O-atom is replaced by other heteroatoms as inoestrone-3-N-sulphamate and oestrone-3-S-sulphamate, these analogues areweaker non-time-dependent inactivators.

In addition to oestrone, the other major steroid with oestrogenicproperties which is produced by postmenopausal women is androstenediol(see FIG. 2).

Androstenediol, although an androgen, can bind to the oestrogen receptor(ER) and can stimulate the growth of ER positive breast cancer cells andthe growth of carcinogen-induced mammary tumours in the rat.Importantly, in postmenopausal women 90% of the androstenediol producedoriginates from the androgen dehydroepiandrosterone sulphate (DHA-S)which is secreted in large amounts by the adrenal cortex. DHA-S isconverted to DHA by DHA sulphatase, which may be the same as, ordifferent from, the enzyme, oestrone sulphatase, which is responsiblefor the hydrolysis of E1S.

During the last 10-15 years considerable research has also been carriedout to develop potent aromatase inhibitors, some of which are nowmarketed. However, in three recent reports of postmenopausal women withbreast cancer who received aromatase inhibitor therapy, plasma E1Sconcentrations remained between 400-1000 pg/ml.

In summation therefore in situ synthesis of oestrogen is thought to makean important contribution to the high levels of oestrogens in tumoursand therefore specific inhibitors of oestrogen biosynthesis are ofpotential value for the treatment of endocrine-dependent tumours.

Moreover, even though oestrogen formation in malignant breast andendometrial tissues via the sulphatase pathway makes a majorcontribution to the high concentration of oestrogens, there are stillother enzymatic pathways that contribute to in vivo synthesis ofoestrogen.

SUMMARY ASPECTS OF THE PRESENT INVENTION

The present invention is based on the surprising finding that thecompounds of the present invention could be used as effective steroidsulphatase (STS) inhibitors; cell cycling modulators; apoptosismodulators; cell growth modulators; glucose uptake prevention and/orsuppression agents; tumour angiogenesis prevention agents or inhibitors;microtubules disruptors; and/or apoptosis inducers.

The compounds of the present invention may comprise other substituents.These other substituents may, for example, further increase the activityof the compounds of the present invention and/or increase stability (exvivo and/or in vivo).

DETAILED ASPECTS OF THE PRESENT INVENTION

According to one aspect of the present invention, there is provided useof a compound in the manufacture of a medicament to prevent and/orinhibit tumour growth, wherein the compound is of Formula I or FormulaII

wherein

A is selected from CR₁₀R₁₁, —S(═O)₂—, —NR₁₂—, and C═O, wherein R₁₀ andR₁₁ independently selected from H, —OH, hydrocarbyl, —CN, —NO₂, andhalogens, R₁₂ is selected from H and hydrocarbyl;

B is selected from (CR₁₃R₁₄)₁₋₃, C═O, CR₁₅R₁₆C═O, —S(═O)₂—, —NR₁₇— and—NR₁₈—C(═O)—, wherein each of R₁₃, R₁₄, R₁₅ and R₁₆ is independentlyselected from H, —OH, hydrocarbyl, —CN, —NO₂, and halogens, R₁₇ and R₁₈are independently selected from H and hydrocarbyl;

R₁ is selected from OH, O-hydrocarbyl, O-heterohydrocarbyl,—SO₂-hydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂,—NR₂₃—C(═O)H and —NR₃₅R₃₆ wherein each of R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₃₅and R₃₆ is independently is selected from H and hydrocarbyl;

R₂ is selected from H, —O-hydrocarbyl, —S-hydrocarbyl, hydrocarbyl, —CN,—NO₂, and halogens,

R₃ is selected from

wherein each of R₄, R₅, R₆, R₇ and R₈ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COOH or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₉, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens, R₉ is selected from H andhydrocarbyl, and each R₂₉ to R₃₃ is independently selected from H andhydrocarbyl; and wherein two or more of R₄, R₅, R₆, R₇, R₈ and R₉ maytogether form a ring;

wherein h is an optional bond,

wherein G is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independently selected from H,—OH, hydrocarbyl, —CN, —NO₂, and halogens, or wherein when h is presentG is CR₂₄, wherein R₂₄ is selected from H, —OH, hydrocarbyl, —CN, —NO₂,and halogens;

n is 0, 1 or 2, each D is independently selected from O, NR₂₆ andCR₂₇R₂₆, wherein each R₂₆ is independently selected from H andhydrocarbyl; and each R₂₇ and R₂₈ is independently selected from H, —OH,hydrocarbyl, —CN, —NO₂, and halogens.

According to one aspect of the present invention, there is provided acompound of Formula I or Formula II

wherein

A is selected from CR₁₀R₁₁, —S(═O)₂—, —NR₁₂—, and C═O, wherein R₁₀ andR₁₁ independently selected from H, —OH, hydrocarbyl, —CN, —NO₂, andhalogens, R₁₂ is selected from H and hydrocarbyl;

B is selected from (CR₁₃R₁₄)₁₋₃, C═O, CR₁₅R₁₆C═O, —S(═O)₂—, —NR₁₇— and—NR₁₈—C(═O)—, wherein each of R₁₃, R₁₄, R₁₅ and R₁₆ is independentlyselected from H, —OH, hydrocarbyl, —CN, —NO₂, and halogens, R₁₇ and R₁₈are independently selected from H and hydrocarbyl;

R₁ is selected from OH, O-hydrocarbyl, O-heterohydrocarbyl,—SO₂-hydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂,—NR₂₃—C(═O)H and —NR₃₅R₃₆ wherein each of R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₃₅and R₃₆ is independently is selected from H and hydrocarbyl;

R₂ is selected from H, —O-hydrocarbyl, —S-hydrocarbyl, hydrocarbyl, —CN,—NO₂, and halogens,

R₃ is selected from

wherein each of R₄, R₅, R₆, R₇ and R₈ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COON or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens, R₉ is selected from H andhydrocarbyl, and each R₂₉ to R₃₃ is independently selected from H andhydrocarbyl; and wherein two or more of R₄, R₅, R₆, R₇, R₈ and R₉ maytogether form a ring;

wherein when R₁ is OH and R₃ is of Formula D, (i) at least one of R₄,R₅, R₆, R₇ and R₈ is independently selected from halocarbyl,—O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, and halogens, or (ii) two or more of R₄, R₅, R₆, R₇and R₈ together form a ring, or (iii) at least three of R₄, R₅, R₆, R₇and R₈ are independently selected from —OH, hydrocarbyl, —O-hydrocarbyl,halocarbyl, —O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens

wherein h is an optional bond,

wherein G is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independently selected from H,—OH, hydrocarbyl, —CN, —NO₂, and halogens, or wherein when h is presentG is CR₂₄, wherein R₂₄ is selected from H, —OH, hydrocarbyl, —CN, —NO₂,and halogens;

n is 0, 1 or 2, each D is independently selected from O, NR₂₆ andCR₂₇R₂₆, wherein each R₂₆ is independently selected from H andhydrocarbyl; and each R₂₇ and R₂₈ is independently selected from H, —OH,hydrocarbyl, —CN, —NO₂, and halogens.

According to one aspect of the present invention, there is provided apharmaceutical composition comprising (a) a compound as defined hereinand (b) a pharmaceutically acceptable carrier, diluent, excipient oradjuvant.

According to one aspect of the present invention, there is provided a(i) compound as defined herein, or (ii) composition as defined herein,for use in medicine.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament to prevent and/or inhibittumour growth.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament for use in the therapy of acondition or disease associated with one or more of steroid sulphatase(STS) activity; carbonic anhydrase (CA) activity; cell cycling;apoptosis; cell growth; glucose uptake by a tumour; tumour angiogenesis;microtubules formation; and apoptosis.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament for use in the therapy of acondition or disease associated with one or more of adverse steroidsulphatase (STS) activity; adverse carbonic anhydrase (CA) activity;cell cycling; apoptosis; cell growth; glucose uptake by a tumour; tumourangiogenesis; microtubules formation; and apoptosis.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament for one or more of inhibitingsteroid sulphatase (STS) activity; inhibiting carbonic anhydrase (CA)activity; modulating cell cycling; modulating apoptosis; modulating cellgrowth; preventing and/or suppressing glucose uptake by a tumour;preventing and/or inhibiting tumour angiogenesis; disruptingmicrotubules; and inducing apoptosis.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament for inhibiting steroidsulphatase (STS) activity.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament for inhibiting carbonicanhydrase (CA) activity.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament for inhibiting and/orpreventing tumour angiogenesis.

According to one aspect of the present invention, there is provided useof (i) a compound as defined herein, or (ii) a composition as definedherein, in the manufacture of a medicament for modulating cell growth.

According to one aspect of the present invention, there is provided amethod of treatment comprising administering to a subject in need oftreatment (i) a compound as defined herein, or (ii) a composition asdefined herein.

According to one aspect of the present invention, there is provided amethod of treatment comprising administering to a subject in need oftreatment (i) a compound as defined herein, or (ii) a composition asdefined herein, in order to inhibit steroid sulphatase (STS) activity;to inhibit carbonic anhydrase (CA) activity, modulate cell cycling;modulate apoptosis; modulate cell growth; prevent and/or suppressglucose uptake by a tumour; prevent and/or inhibit tumour angiogenesis;disrupt microtubules; and/or induce apoptosis.

According to one aspect of the present invention, there is provided amethod comprising (a) performing an assay for one or more of steroidsulphatase (STS) inhibition; carbonic anhydrase (CA) inhibition, cellcycling modulation; apoptosis modulation; cell growth modulation;prevention and/or suppression of glucose uptake by a tumour; tumourangiogenesis prevention and/or inhibition; microtubules disruption; andapoptosis induction, with one or more candidate compounds definedherein; (b) determining whether one or more of said candidate compoundsis/are capable of one or more of steroid sulphatase (STS) inhibition;carbonic anhydrase (CA) inhibition, cell cycling modulation; apoptosismodulation; cell growth modulation; prevention and/or suppression ofglucose uptake by a tumour; tumour angiogenesis prevention and/orinhibition; microtubules disruption; and apoptosis induction; and (c)selecting one or more of said candidate compounds that is/are capable ofone or more of steroid sulphatase (STS) inhibition; carbonic anhydrase(CA) inhibition, cell cycling modulation; apoptosis modulation; cellgrowth modulation; prevention and/or suppression of glucose uptake by atumour; tumour angiogenesis prevention and/or inhibition; microtubulesdisruption; and apoptosis induction.

In any one of the methods of the present invention, one or moreadditional steps may be present. For example, the method may alsoinclude the step of modifying the identified candidate compound (such asby chemical and/or enzymatic techniques) and the optional additionalstep of testing that modified compound for one or more of steroidsulphatase (STS) inhibition; carbonic anhydrase (CA) inhibition, cellcycling modulation; apoptosis modulation; cell growth modulation;prevention and/or suppression of glucose uptake by a tumour; tumourangiogenesis prevention and/or inhibition; microtubules disruption; andapoptosis induction. By way of further example, the method may alsoinclude the step of determining the structure (such as by use ofcrystallographic techniques) of the identified candidate compound andthen performing computer modeling studies—such as to further increaseits action. Thus, the present invention also encompasses a computerhaving a dataset (such as the crystallographic co-ordinates) for saididentified candidate compound. The present invention also encompassesthat identified candidate compound when presented on a computer screenfor the analysis thereof—such as enzyme and/or protein binding studies.

According to one aspect of the present invention, there is provided acompound identified by the method of the present invention.

The present invention also encompasses the novel compounds of thepresent invention (such as those presented herein), as well as processesfor making same (such as the processes presented herein) as well asnovel intermediates (such as those presented herein) for use in thoseprocesses.

For ease of reference, these and further aspects of the presentinvention are now discussed under appropriate section headings. However,the teachings under each section are not necessarily limited to eachparticular section.

Some Advantages

One key advantage of the present invention is that the compounds of thepresent invention can prevent and/or inhibit tumour angiogenesis.

One key advantage of the present invention is that the compounds of thepresent invention can modulate cell cycling.

One key advantage of the present invention is that the compounds of thepresent invention can modulate apoptosis.

One key advantage of the present invention is that the compounds of thepresent invention can modulate cell growth.

One key advantage of the present invention is that the compounds of thepresent invention can prevent and/or suppress glucose uptake by atumour.

One key advantage of the present invention is that the compounds of thepresent invention can inhibit steroid sulphatase (STS) activity.

One key advantage of the present invention is that the compounds of thepresent invention can disrupt microtubules.

In this respect, microtubules, together with microfilaments andintermediate filaments form part of the cytoskeletal system of a cell.Microtubules are responsible for many of cell movements-examples includethe beating of cilia and flagella and the transport of membrane vesiclesin the cytoplasm. All these movements result from the polymerisation anddepolymerisation of microtubules or the actions of the microtubule motorproteins dynein and kinesins. Some other cell movements, such as thealignment and separation of chromosomes during meiosis and mitosisresult from both mechanisms. Microtubules also direct cell movement butin some cases, microtubules serve purely structural functions.

A microtubule is composed of subunits that are heterodimers of α-tubulinand β-tubulin monomers. There are two populations of microtubules:stable, long-lived microtubules and dynamic, short lived microtubules.Dynamic microtubules are found when the microtubule structures need toassemble and dissemble quickly. For example, during mitosis, thecytosolic microtubule network characteristic of interphase cellsdisappears and the tubulin from it is used to form the spindle apparatuswhich partitions chromosomes equally to the daughter cells. When mitosisis complete, the spindle disassembles and the interphase microtubulenetwork reforms.

Drugs that inhibit mitosis provide a useful means to manipulate themicrotubules in a cell. Three drugs: colchicine, vinblastine andtaxol—all purified from plants—have proved to be very powerful probes ofmicrotubule function partly because they bind only to tubulin ormicrotubules and not to other proteins and also because theirconcentrations in cells can be easily controlled.

Because of their effects on mitosis, microtubule inhibitors have beenwidely used to treat illness and more recently as anticancer agents,since blockage of spindle formation will preferentially inhibit rapidlydividing cells like cancer cells. A highly effective anti-ovarian canceragent is taxol. In ovarian cancer cells, which undergo rapid celldivisions, mitosis is blocked by taxol treatment while other functionscarried out by intact microtubules are not affected. A comprehensivereview of microtubules can be found in “Molecular Cell Biology” (Ed:Lodish et at 1995 WH Freeman and Co. New York pp 1051-1122).

One key advantage of the present invention is that the compounds of thepresent invention can induce apoptosis.

Apoptosis is induced by MT-targeting drugs, a process which may involvethe phosphorylation (and inactivation) of the apoptosis regulator, thebcl-2 protein (Halder, Cancer Res. 57: 229, 1997).

The present invention is based on the surprising finding that thecompound provides an effective treatment of cancer.

Another advantage of the compounds of the present invention is that theymay be potent in vivo.

Some of the compounds of the present invention may be non-oestrogeniccompounds. Here, the term “non-oestrogenic” means exhibiting no orsubstantially no oestrogenic activity. Here, by the term“non-oestrogenic” means exhibiting no or substantially no systemicoestrogenic activity, such as that determined by Protocol 4.

For some applications, the compounds have an oestrogenic effect.

Another advantage is that some of the compounds may not be capable ofbeing metabolised to compounds which display or induce hormonalactivity.

For some applications, preferably the compounds have a reversibleaction. For some applications, preferably the compounds have anirreversible action. Some of the compounds of the present invention arealso advantageous in that they may be orally active.

Some of the compounds of the present invention may useful for theprevention and/or treatment of cancer, such as breast cancer, as well as(or in the alternative) non-malignant conditions, such as the preventionand/or treatment of inflammatory conditions—such as conditionsassociated with any one or more of: autoimmunity, including for example,rheumatoid arthritis, type I and II diabetes, systemic lupuserythematosus, multiple sclerosis, myasthenia gravis, thyroiditis,vasculitis, ulcerative colitis and Crohn's disease, skin disorders e.g.acne, psoriasis and contact dermatitis; graft versus host disease;eczema; asthma and organ rejection following transplantation. Thecompounds of the present invention are useful particularly whenpharmaceuticals may need to be administered from an early age.

In one embodiment, the compounds of the present invention are useful forthe treatment of breast cancer.

Thus, some of the compounds of the present invention are also believedto have therapeutic uses other than for the treatment ofendocrine-dependent cancers, such as the treatment of autoimmunediseases.

For ease of reference, these and further aspects of the presentinvention are now discussed under appropriate section headings. However,the teachings under each section are not necessarily limited to eachparticular section.

Preferable Aspects

Use

As described above the present invention provides use of a compound inthe manufacture of a medicament to prevent and/or inhibit tumour growth,wherein the compound is of Formula I or Formula II

wherein

A is selected from CR₁₀R₁₁, —S(═O)₂—, —NR₁₂—, and C═O, wherein R₁₀ andR₁₁ independently selected from H, —OH, hydrocarbyl, —CN, —NO₂, andhalogens, R₁₂ is selected from H and hydrocarbyl;

B is selected from (CR₁₃R₁₄)₁₋₃, C═O, CR₁₅R₁₆C═O, —S(═O)₂—, —NR₁₇— and—NR₁₈—C(═O)—, wherein each of R₁₃, R₁₄, R₁₅ and R₁₆ is independentlyselected from H, —OH, hydrocarbyl, —CN, —NO₂, and halogens, R₁₇ and R₁₈are independently selected from H and hydrocarbyl;

R₁ is selected from OH, O-hydrocarbyl, O-heterohydrocarbyl,—SO₂-hydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂,—NR₂₃—C(═O)H and —NR₃₅R₃₆ wherein each of R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₃₅and R₃₆ is independently is selected from H and hydrocarbyl;

R₂ is selected from H, —O-hydrocarbyl, —S-hydrocarbyl, hydrocarbyl, —CN,—NO₂, and halogens,

R₃ is selected from

wherein each of R₄, R₆, R₆, R₇ and R₈ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COOH or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR_(3o)R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens, R₉ is selected from H andhydrocarbyl, and each R₂₉ to R₃₃ is independently selected from H andhydrocarbyl; and wherein two or more of R₄, R₅, R₆, R₇, R₈ and R₉ maytogether form a ring;

wherein h is an optional bond,

wherein G is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independently selected from H,—OH, hydrocarbyl, —CN, —NO₂, and halogens, or wherein when h is presentG is CR₂₄, wherein R₂₄ is selected from H, —OH, hydrocarbyl, —CN, —NO₂,and halogens;

n is 0, 1 or 2, each D is independently selected from O, NR₂₆ andCR₂₇R₂₈, wherein each R₂₆ is independently selected from H andhydrocarbyl; and each R₂₇ and R₂₅ is independently selected from H, —OH,hydrocarbyl, —CN, —NO₂, and halogens.

In this aspect preferably R₁ is selected from OH, O-hydrocarbyl,O-heterohydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂,—NR₂₃—C(═O)H and —NR₃₅R₃₆

Preferably when R₁ is OH and R₃ is of Formula D, (i) at least one of R₄,R₆, R₆, R₇ and R₈ is independently selected from halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, and halogens, or (ii) two or more of R₄, R₅, R₆, R₇and R₈ together form a ring, or (iii) at least three of R₄, R₆, R₆, R₇and R₈ are independently selected from —OH, hydrocarbyl, —O-hydrocarbyl,halocarbyl, —O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens.

The term “halocarbyl” as used herein means a group comprising at least Cand halogen and may optionally comprise H and/or one or more othersuitable substituents. Examples of such substituents may include halo-,alkoxy-, nitro-, a hydrocarbon group, an N-acyl group, a cyclic groupetc. In addition to the possibility of the substituents being a cyclicgroup, a combination of substituents may form a cyclic group. If thehalocarbyl group comprises more than one C then those carbons need notnecessarily be linked to each other. For example, at least two of thecarbons may be linked via a suitable element or group. Thus, thehalocarbyl group may contain hetero atoms. Suitable hetero atoms will beapparent to those skilled in the art and include, for instance, sulphur,nitrogen and oxygen. In one preferred aspect the “halocarbyl” is ahalohydrocarbyl group, that is a group comprising at least C, halogenand H and may comprises one or more other suitable substituents, such asthose listed herein.

The term “heterohydrocarbyl” as used herein means a group comprising atleast C, H and one of sulphur, nitrogen and oxygen and may optionallycomprises one or more other suitable substituents. Examples of suchsubstituents may include halo-, alkoxy-, nitro-, a hydrocarbon group, anN-acyl group, a cyclic group etc. In addition to the possibility of thesubstituents being a cyclic group, a combination of substituents mayform a cyclic group. If the halocarbyl group comprises more than one Cthen those carbons need not necessarily be linked to each other. Forexample, at least two of the carbons may be linked via a suitableelement or group.

The term “hydrocarbyl group” as used herein means a group comprising atleast C and H and may optionally comprise one or more other suitablesubstituents. Examples of such substituents may include halo-, alkoxy-,nitro-, a hydrocarbon group, an N-acyl group, a cyclic group etc. Inaddition to the possibility of the substituents being a cyclic group, acombination of substituents may form a cyclic group. If the hydrocarbylgroup comprises more than one C then those carbons need not necessarilybe linked to each other. For example, at least two of the carbons may belinked via a suitable element or group. Thus, the hydrocarbyl group maycontain hetero atoms. Suitable hetero atoms will be apparent to thoseskilled in the art and include, for instance, sulphur, nitrogen andoxygen.

Compound

As described above the present invention provides a compound of FormulaI or Formula II

wherein

A is selected from CR₁₀R₁₁, —S(═O)₂—, —NR₁₂—, and C′O, wherein R₁₀ andR₁₁ independently selected from H, —OH, hydrocarbyl, —CN, —NO₂, andhalogens, R₁₂ is selected from H and hydrocarbyl;

B is selected from (CR₁₃R₁₄)₁₋₃, C═O, CR₁₅R₁₆C═O, —S(═O)₂—, —NR₁₇— and—NR₁₆—C(═O)—, wherein each of R₁₃, R₁₄, R₁₅ and R₁₆ is independentlyselected from H, —OH, hydrocarbyl, —CN, —NO₂, and halogens, R₁₇ and R₁₈are independently selected from H and hydrocarbyl;

R₁ is selected from OH, O-hydrocarbyl, O-heterohydrocarbyl,—SO₂-hydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂,—NR₂₃—C(═O)H and —NR₃₅R_(36 wherein each of R) ₁₉, R₂₀, R₂₁, R₂₂, R₂₃,R₃₅ and R₃₆ is independently is selected from H and hydrocarbyl;

R₂ is selected from H, —O-hydrocarbyl, —S-hydrocarbyl, hydrocarbyl, —CN,—NO₂, and halogens,

R₃ is selected from

wherein each of R₄, R₅, R₆, R₇ and R₈ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COON or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens, R₉ is selected from H andhydrocarbyl, and each R₂₉ to R₃₃ is independently selected from H andhydrocarbyl; and wherein two or more of R₄, R₅, R₆, R₇, R₈ and R₉ maytogether form a ring;

wherein when R₁ is OH and R₃ is of Formula D, (i) at least one of R₄,R₅, R₆, R₇ and R₈ is independently selected from halocarbyl,—O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, and halogens, or (ii) two or more of R₄, R₅, R₆, R₇and R₈ together form a ring, or (iii) at least three of R₄, R₅, R₆, R₇and R₈ are independently selected from —OH, hydrocarbyl, —O-hydrocarbyl,halocarbyl, —O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens

wherein h is an optional bond,

wherein G is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independently selected from H,—OH, hydrocarbyl, —CN, —NO₂, and halogens, or wherein when h is presentG is CR₂₄, wherein R₂₄ is selected from H, —OH, hydrocarbyl, —CN, —NO₂,and halogens;

n is 0, 1 or 2, each D is independently selected from O, NR₂₆ andCR₂₇R₂₈, wherein each R₂₆ is independently selected from H andhydrocarbyl; and each R₂₇ and R₂₈ is independently selected from H, —OH,hydrocarbyl, —CN, —NO₂, and halogens

In one preferred aspect the compound is capable of one or more ofinhibiting steroid sulphatase (STS) activity; modulating cell cycling;modulating apoptosis; modulating cell growth; preventing and/orsuppressing glucose uptake by a tumour; preventing and/or inhibitingtumour angiogenesis; disrupting microtubules; and inducing apoptosis.

In one preferred embodiment of the present invention, one or more of thehydrocarbyl groups is a hydrocarbon group. In one preferred embodimentof the present invention, each hydrocarbyl group is a hydrocarbon group.

Here the term “hydrocarbon” means any one of an alkyl group, an alkenylgroup, an alkynyl group, an acyl group, which groups may be linear,branched or cyclic, or an aryl group. The term hydrocarbon also includesthose groups but wherein they have been optionally substituted. If thehydrocarbon is a branched structure having substituent(s) thereon, thenthe substitution may be on either the hydrocarbon backbone or on thebranch; alternatively the substitutions may be on the hydrocarbonbackbone and on the branch.

The alkyl group may be selected from one of C₁-C₂₀ alkyl, C₁-C₁₀ alkyl,C₁-C₅ alkyl, and C₁-C₃ alkyl. In one aspect the alkyl group is C₁₋₁₀alkyl. In one aspect the alkyl group is C₁₋₅ alkyl. In one aspect thealkyl group is C₁₋₃ alkyl. Preferred alkyl groups are —CH₃ and —CH₂CH₃.

In one preferred embodiment of the present invention, one or more of thehydrocarbyl groups is an oxyhydrocarbyl group. In one preferredembodiment of the present invention, each hydrocarbyl group is anoxyhydrocarbyl group.

The term “oxyhydrocarbyl group” as used herein means a group comprisingat least C, H and O and may optionally comprise one or more othersuitable substituents. Examples of such substituents may include halo-,alkoxy-, nitro-, an alkyl group, a cyclic group etc. In addition to thepossibility of the substituents being a cyclic group, a combination ofsubstituents may form a cyclic group. If the oxyhydrocarbyl groupcomprises more than one C then those carbons need not necessarily belinked to each other. For example, at least two of the carbons may belinked via a suitable element or group. Thus, the oxyhydrocarbyl groupmay contain hetero atoms. Suitable hetero atoms will be apparent tothose skilled in the art and include, for instance, sulphur andnitrogen.

In one preferred embodiment of the present invention, the or each or oneor more of the oxyhydrocarbyl groups is a oxyhydrocarbon group.

Here the term “oxyhydrocarbon” means any one of an alkoxy group, anoxyalkenyl group, an oxyalkynyl group, which groups may be linear,branched or cyclic, or an oxyaryl group. The term oxyhydrocarbon alsoincludes those groups but wherein they have been optionally substituted.If the oxyhydrocarbon is a branched structure having substituent(s)thereon, then the substitution may be on either the hydrocarbon backboneor on the branch; alternatively the substitutions may be on thehydrocarbon backbone and on the branch.

Preferably the oxyhydrocarbyl group is an alkoxy group. Preferably theoxyhydrocarbyl group is of the formula C₁₋₆O (such as a C₁₋₃O).

In one aspect the compounds is of Formula II

Preferably the compound is of Formula I

A

As discussed herein A is selected from CR₁₀R₁₁, —S(═O)₂—, —NR₁₂—, andC═O, wherein R₁₀ and R₁₁ independently selected from H, —OH,hydrocarbyl, —CN, —NO₂, and halogens, R₁₂ is selected from H andhydrocarbyl.

In a preferred aspect A is selected from CR₁₀R₁₁ and C═O, wherein R₁₀and R₁₁ independently selected from H, —OH, hydrocarbyl, —CN, —NO₂, andhalogens. More preferably A is selected from CR₁₀R₁₁ and C═O, whereinR₁₀ and R₁₁ independently selected from H, —OH, hydrocarbyl andhalogens, for example A may be is selected from CH₂ and C═O.

B

As discussed herein B is selected from (CR₁₃R₁₄)₁₋₃, C═O, CR₁₅R₁6C═O,—S(═O)₂—, —NR₁₇— and —NR₁₅—C(═O)—, wherein each of R₁₃, R₁₄, R₁₅ and R₁₆is independently selected from H, —OH, hydrocarbyl, —CN, —NO₂, andhalogens, R₁₇ and R₁₈ are independently selected from H and hydrocarbyl;

In one preferred aspect B is selected from (CR₁₃R₁₄)₁₋₃, C═O, and—S(═O)₂—, wherein each of R₁₃ and R₁₄, is independently selected from H,—OH, hydrocarbyl, —CN, —NO₂, and halogens. Preferably B is selected fromCR₁₃R₁₄, C═O, and —S(═O)₂—, wherein each of R₁₃ and R₁₄, isindependently selected from H, —OH, hydrocarbyl, —CN, —NO₂, andhalogens. More preferably B is selected from (CH₂)₁₋₃, C═O, and—S(═O)₂—, such as CH₂, C═O, and —S(═O)₂—.

Preferably each of R₁₃ and R₁₄ is independently selected from H andhydrocarbyl. In one aspect each of R₁₃ and R₁₄ is independently selectedhydrocarbyl. In one preferred embodiment of the present invention eachof R₁₃ and R₁₄ is independently selected from one of H, C₁-C₂₀hydrocarbyl, C₁-C₁₀ hydrocarbyl, C₁-C₅ hydrocarbyl, C₁-C₃ hydrocarbyl,hydrocarbon groups, C₁-C₂₀ hydrocarbon, C₁-C₁₀ hydrocarbon, C₁-C₅hydrocarbon, C₁-C₃ hydrocarbon, alkyl groups, C₁-C₂₀ alkyl, C₁-C₁₀alkyl, C₁-C₅ alkyl, and C₁-C₃ alkyl.

In one aspect each of R₁₃ and R₁₄ is independently selected from H andC₁₋₁₀ alkyl. In one aspect each of R₁₃ and R₁₄ is independently selectedfrom C₁₋₁₀ alkyl. In one aspect each of R₁₃ and R₁₄ is independentlyselected from H and C₁₋₅ alkyl. In one aspect each of R₁₃ and R₁₄ isindependently selected from C₁₋₅ alkyl. In one aspect each of R₁₃ andR₁₄ is independently selected from H and C₁₋₃ alkyl. In one aspect R⁵ isC₁₋₃ alkyl. Preferably each of R₁₃ and R₁₄ is —CH₃.

R1

As discussed herein, R₁ is selected from OH, O-hydrocarbyl,O-heterohydrocarbyl, —SO₂-hydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₉R₂₀,—C(═O)—NR₂₁R₂₂, —NR₂₃—C(═O)H and —NR₃₆R_(36 wherein each of R) ₁₉, R₂₀,R₂₁, R₂₂, R₂3, R35 and R₃₆ is independently is selected from H andhydrocarbyl.

In one aspect, R₁ is selected from OH, O-heterohydrocarbyl,—SO₂-hydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₆R₂₀, —C(═O)—NR₂₁R₂₂,—NR₂₃—C(═O)H and —NR₃₅R₃₆ wherein each of R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₃₅and R₃₆ is independently is selected from H and hydrocarbyl.

In one preferred aspect R₁ is selected from OH, O-heterohydrocarbyl, and—OSO₂NR₁₉R₂₀, wherein each of R₁₉ and R₂₀ is independently is selectedfrom H and hydrocarbyl.

In one aspect R¹ is a —OSO₂NR₁₆R₂₀ group, namely a sulphamate group.

The term “sulphamate” includes an ester of sulphamic acid, or an esterof an N-substituted derivative of sulphamic acid, or a salt thereof.

In one aspect R¹ is a sulphamate group. In this aspect the compound ofthe present invention may be referred to as a sulphamate compound.

Preferably the sulphamate group of R¹, is a sulphamate group of theformula

wherein R₁₉ and R₂₀ are independently selected from H or a hydrocarbylgroup.

Preferably R₁₉ and R₂₀ are independently selected from H, alkyl,cycloalkyl, alkenyl, acyl and aryl, or combinations thereof, or togetherrepresent alkylene, wherein the or each alkyl or cycloalkyl or alkenylor aryl optionally contains one or more hetero atoms or groups.

When substituted, the N-substituted compounds of this invention maycontain one or two N-alkyl, N-alkenyl, N-cycloalkyl, N-acyl, or N-arylsubstituents, preferably containing or each containing a maximum of 10carbon atoms. When R₁₉ and/or R₂₀ is alkyl, the preferred values arethose where R₁₉ and R₂₀ are each independently selected from lower alkylgroups containing from 1 to 5 carbon atoms, that is to say methyl,ethyl, propyl etc. Preferably R₁₉ and R₂₀ are both methyl. When R₁₉and/or R₂₀ is aryl, typical values are phenyl and tolyl (-PhCH₃; o-, m-or p-). Where R₁₉ and R₂₀ represent cycloalkyl, typical values arecyclopropyl, cyclopentyl, cyclohexyl etc. When joined together R₁₉ andR₂₀ typically represent an alkylene group providing a chain of 4 to 6carbon atoms, optionally interrupted by one or more hetero atoms orgroups, e.g. —O— or —NH— to provide a 5-, 6- or 7-membered heterocycle,e.g. morpholino, pyrrolidino or piperidino.

Within the values alkyl, cycloalkyl, alkenyl, acyl and aryl we includesubstituted groups containing as substituents therein one or more groupswhich do not interfere with the sulphatase inhibitory activity of thecompound in question. Exemplary non-interfering substituents includehydroxy, amino, halo, alkoxy, alkyl and aryl. A non-limiting example ofa hydrocarbyl group is an acyl group.

In some embodiments, the sulphamate group may form a ring structure bybeing fused to (or associated with) one or more atoms in or on thesteroidal ring system.

In some embodiments, there may be more than one sulphamate group. By wayof example, there may be two sulphamates (i.e. bis-sulphamatecompounds).

In some preferred embodiments, at least one of R₁₉ and R₂₀ is H.

In some preferred embodiments, each of R₁₉ and R₂₀ is H.

In some preferred embodiments R¹ is a sulphamate group and the compoundis suitable for use as an inhibitor of oestrone sulphatase (E.C.3.1.6.2).

In some preferred embodiments if the sulphamate group on the sulphamatecompound were to be replaced with a sulphate group to form a sulphatecompound then the sulphate compound would be hydrolysable by a steroidsulphatase enzyme (E.C.3.1.6.2).

In some preferred embodiments if the sulphamate group on the sulphamatecompound were to be replaced with a sulphate group to form a sulphatecompound and incubated with a steroid sulphatase enzyme (E.C.3.1.6.2) ata pH 7.4 and 37° C. it would provide a K_(m) value of less than 50 mM.

In some preferred embodiments if the sulphamate group on the sulphamatecompound were to be replaced with a sulphate group to form a sulphatecompound and incubated with a steroid sulphatase enzyme (E.C.3.1.6.2) ata pH 7.4 and 37° C. it would provide a K_(m) value of less than 50 μM.

O-hydrocarbyl

In one preferred aspect R₁ is O-hydrocarbyl.

Preferably R₁ is selected from or the O-hydrocarbyl group is selectedfrom O-aryl groups such as an O-phenyl and O-benzyl groups, and O-alkylgroups.

Preferably R₁ is selected from or the O-hydrocarbyl group is selectedfrom an alkyl group and a benzyl.

The hydrocarbyl of the O-hydrocarbyl group may be selected from one ofC₁-C₂₀ hydrocarbyl, C₁-C₁₀ hydrocarbyl, C₁-C₅ hydrocarbyl, C₁-C₃hydrocarbyl, hydrocarbon groups, C₁-C₂₀ hydrocarbon, C₁-C₁₀ hydrocarbon,C₁-C₅ hydrocarbon, C₁-C₃ hydrocarbon, alkyl groups, C₁-C₂₀ alkyl, C₁-C₁₀alkyl, C₁-C₅ alkyl, and C₁-C₃ alkyl.

O-heterohydrocarbyl

In one preferred aspect R₁ is O-heterohydrocarbyl.

Preferably R₁ is selected from or the O-heterohydrocarbyl group isselected from O-acyl groups such as an O-acetyl group.

Preferably R₁ is selected from or the O-heterohydrocarbyl group isselected from an alkoxy benzyl group. Preferably the alkoxy benzyl groupis a C1-6 alkoxy benzyl group. More preferably the alkoxy benzyl groupis a methoxy benzyl group, such as a 2-methoxy benzyl group or a3-methoxy benzyl group.

In one preferred aspect R₁ is selected from OH, O-acetyl group —OSO₂NH₂,and methoxy benzyl groups.

—OC(═O)NR₂₁R₂₂

In one preferred aspect R₁ is —OC(═O)NR₂₁R₂₂, wherein R₂₁ and R₂₂ areindependently selected from H and hydrocarbyl

Preferably R₂₁ and R₂₂ are independently selected from H andhydrocarbyl. In one aspect R₂₁ and R₂₂ are independently selected fromhydrocarbyl. In one preferred embodiment of the present invention R₂₁and R₂₂ are independently selected from one of H, C₁-C₂₀ hydrocarbyl,hydrocarbyl, C₁-C₅ hydrocarbyl, C₁-C₃ hydrocarbyl, hydrocarbon groups,C₁-C₂₀ hydrocarbon, C₁-C₁₀ hydrocarbon, C₁-C₅ hydrocarbon, C₁-C₃hydrocarbon, alkyl groups, C₁-C₂₀ alkyl, C₁-C₁₅ alkyl, C₁-C₅ alkyl, andC₁-C₃ alkyl.

In one aspect R₂₁ and R₂₂ are independently selected from H and C₁₋₁₀alkyl. In one aspect R₂₁ and R₂₂ are independently selected from C₁₋₁₀alkyl. In one aspect R₂₁ and R₂₂ are independently selected from H andC₁₋₅ alkyl. In one aspect R₂₁ and R₂₂ are independently selected fromC₁₋₅ alkyl. In one aspect R₂₁ and R₂₂ are independently selected from Hand C₁₋₃ alkyl. In one aspect R₂₁ and R₂₂ are independently selectedfrom C₁₋₃ alkyl. Preferably R₂₁ and R₂₂ are both H.

R₂

As discussed herein R₂ is selected from H, —O-hydrocarbyl,—S-hydrocarbyl, hydrocarbyl, —CN, —NO₂, and halogens,

In one preferred aspect R₂ is selected from —O-hydrocarbyl groups.Preferably the —O-hydrocarbyl group is an alkoxy group. Preferably R₂ isof the formula CO₁₋₆ (such as a C₁₋₃O). Preferably R₂ is of the formula—O(CH₂)₁₋₁₀CH₃, —O(CH₂)₁₋₅CH₃, —O(CH₂)₁₋₂CH₃. In a highly preferredaspect R₂ is methoxy.

In one preferred embodiment of the present invention, R₂ is ahydrocarbon group. Preferably R₂ is an alkyl group. Preferably the alkylgroup is a C₁₋₆ alkyl group (such as a C₁₋₃ alkyl group). Preferably thehydrocarbyl group R₂ is of the formula —(CH₂)₁₋₁₀CH₃, —(CH₂)₁₋₅CH₃,—(CH₂)₁₋₂CH₃. In a highly preferred aspect R₂ is ethyl.

In one preferred embodiment of the present invention R₂ is selected fromone of C₁-C₁₀ hydrocarbyl, C₁-C₅ hydrocarbyl, C₁-C₃ hydrocarbyl,hydrocarbon groups, C₁-C₁₀ hydrocarbon, C₁-C₅ hydrocarbon, C₁-C₃hydrocarbon, alkyl groups, C₁-C₁₀ alkyl, C₁-C₅ alkyl, and C₁-C₃ alkyl.

In one preferred embodiment of the present invention, the R₂ is ahydrocarbylsulphanyl group such as a —S-hydrocarbyl group.

The term “hydrocarbylsulphanyl” means a group that comprises at leasthydrocarbyl group (as herein defined) and sulphur. That sulphur groupmay be optionally oxidised. Preferably the hydrocarbylsulphanyl is ofthe formula —S-hydrocarbyl wherein the hydrocarbyl is as describedherein.

The term “hydrocarbylsulphanyl group” as used herein with respect to R₂means a group comprising at least C, H and S and may optionally compriseone or more other suitable substituents. Examples of such substituentsmay include halo-, alkoxy-, nitro-, an alkyl group, a cyclic group etc.In addition to the possibility of the substituents being a cyclic group,a combination of substituents may form a cyclic group. If thehydrocarbylsulphanyl group comprises more than one C then those carbonsneed not necessarily be linked to each other. For example, at least twoof the carbons may be linked via a suitable element or group. Thus, thehydrocarbylsulphanyl group may contain further hetero atoms. Suitablehetero atoms will be apparent to those skilled in the art and include,for instance, nitrogen.

In one preferred embodiment of the present invention, the R₂ is ahydrocarbonsulphanyl group. The term “hydrocarbonsulphanyl group” asused herein with respect to R₂ means a group consisting of C, H and S.Preferably the hydrocarbonsulphanyl is of the formula —S-hydrocarbonwherein the hydrocarbon is as described herein.

Preferably the hydrocarbonsulphanyl group R₂ is of the formula C₁₋₆S(such as a C₁₋₃S). Preferably the oxyhydrocarbyl group R₂ is of theformula —S(CH₂)₁₋₁₀CH₃, —S(CH₂)₁₋₅CH₃, —S(CH₂)₁₋₂CH₃. In a highlypreferred aspect R₂ is —S-Me.

R3

In one aspect R₃ is a group of Formula A

wherein each of R₄, R₅, R₆, R₇ and R₈ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COOH or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens,

wherein each R₂₉ to R₃₃ is independently selected from H andhydrocarbyl; and wherein two or more of R₄, R₅, R₆, R₇, R₈ and R₉ maytogether form a ring.

In one aspect R3 is a group of Formula B

wherein each of R₄, R₅, R₆, and R₇ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COOH or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₉, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens,

R₉ is selected from H and hydrocarbyl, and each R₂₉ to R₃₃ isindependently selected from H and hydrocarbyl; and wherein two or moreof R₄, R₅, R₆, R₇, and R₉ may together form a ring.

In one aspect R₃ is a group of Formula C

wherein each of R₄, R₅, R₆, and R₈ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COOH or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens,

R₉ is selected from H and hydrocarbyl, and each R₂₉ to R₃₃ isindependently selected from H and hydrocarbyl; and wherein two or moreof R₄, R₅, R₆, R₈, and R₉ may together form a ring.

In one aspect R₃ is a group of Formula D

wherein each of R₄, R₅, R₇, and R₈ is independently selected from H,—OH, hydrocarbyl, —O-hydrocarbyl, —COOH or an ester thereof, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens, R₉ is selected from H andhydrocarbyl, and each R₂₉ to R₃₃ is independently selected from H andhydrocarbyl; and wherein two or more of R₄, R₅, R₇, R₈, and R₉ maytogether form a ring.

R₄, R₅, R₆, R₇ and R₈

As discussed herein, each of R₄, R₅, R₇, R₈, and R₉ is independentlyselected from H, —OH, hydrocarbyl, —O-hydrocarbyl, —COOH or an esterthereof, halocarbyl, —O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl,—O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens.

In one aspect each of R₄, R₅, R₆, R₇ and R₈ is independently selectedfrom H, —OH, C1-6 alkyl, C1-6 aryl, —O—C1-6 alkyl, —O—C1-6 aryl, —COOHor a C1-6 alkyl ester thereof, C1-6 halocarbyl, —O—C1-6 halocarbyl,—O-acetyl, —NR₂₉-acetyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN,—NO₂, and halogens, wherein each R₂₉ to R₃₃ is independently selectedfrom H and C1-6 alkyl

In one aspect each of R₄, R₅, R₆, R₇ and R₈ is independently selectedfrom H, —OH, C1-6 alkyl, C1-6 aryl, —O—C1-6 alkyl, —O—C1-6 aryl, —COOHor a C1-6 alkyl ester thereof, C1-6 halocarbyl, —O—C1-6 halocarbyl,—O-acetyl, —NH-acetyl, —O—SO₂NH₂, —NH₂, —NH—SO₂—NH₂, —CN, —NO₂, andhalogens.

In one aspect each of R₄, R₅, R₆, R₇ and R₈ is independently selectedfrom H, —OH, Me, Et, —OMe, —OEt, —OPh, —O-iPr, —COOMe, —CF₃, —OCF₃, F,Cl, —O-acetyl, —NH-acetyl, —O—SO₂NH₂, —NH₂, —NH—SO₂—NH₂, —CN, and —NO₂.

In one aspect each of R₄, R₅, R₆, R₇ and R₆ is independently selectedfrom H, —OH, Me, —OMe, —OEt, —OPh, —O-iPr, —COOMe, —CF₃, —OCF₃, F, Cl,—O-acetyl, —NH-acetyl, —O—SO₂NH₂, —NH₂, —NH—SO₂—NH₂, —CN, and —NO₂.

In one aspect R₄ is selected from H, —OH, —O-hydrocarbyl, —COOH or asalt thereof, and —CN.

In one aspect R₄ is selected from H, —OH, —OMe, —COOH and —CN.

In one aspect R₅ is selected from H, —OH, hydrocarbyl, —O-hydrocarbyl,halocarbyl, —O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀,—NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens.

In one aspect R₅ is selected from H, —OH, Me, Et, —OMe, —OEt, —OPh,—O-iPr, —CF₃, —OCF₃, F, Cl, —O-acetyl, —NH-acetyl, —O—SO₂NH₂, —NH₂,—NH—SO₂—NH₂, —CN, and —NO₂.

In one aspect R₅ is selected from H, —OH, Me, —OMe, —OEt, —OPh, —O-iPr,—CF₃, —OCF₃, F, Cl, —O-acetyl, —NH-acetyl, —O—SO₂NH₂, —NH₂, —NH—SO₂—NH₂,—CN, and —NO₂.

In one aspect R₆ is selected from H, —O-hydrocarbyl and —CN.

In one aspect R₆ is selected from H, —OMe, and —CN.

In one aspect R₇ is selected from H, and —O-hydrocarbyl.

In one aspect R₇ is selected from H and —OMe.

In one aspect R₉ is H.

In one aspect R₉ is selected from H and C1-6 alkyl.

In one preferred aspect at least one of R₄, R₅, R₆, R₇ and R₈ isindependently selected from halocarbyl, —O-halocarbyl, —O-acyl,—NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, and halogens,

R₂₉ to R₃₃

Preferably each R₂₉ to R₃₃ is independently selected from H and C1-6alkyl.

h

In one preferred aspect optional bond h is not present.

G

As discussed herein G is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independentlyselected from H, —OH, hydrocarbyl, —CN, —NO₂, and halogens, or whereinwhen h is present G is CR₂₄, wherein R₂₄ is selected from H, —OH,hydrocarbyl, —CN, —NO₂, and halogens.

In one preferred aspect G is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independentlyselected from H and hydrocarbyl, or wherein when h is present G is CR₂₄,wherein R₂₄ is selected from H and hydrocarbyl. Preferably G is CR₂₄R₂₅,wherein R₂₄ and R₂₅ independently selected from H and C1-6 alkyl, orwherein when h is present G is CR₂₄, wherein R₂₄ is selected from H andC1-6 alkyl. More preferably CR₂₄R₂₅, wherein R₂₄ and R₂₅ independentlyselected from H, Et and Me, or wherein when h is present G is CR₂₄,wherein R₂₄ is selected from H and Me. More preferably G is CR₂₄R₂₅,wherein R₂₄ and R₂₅ independently selected from H and Me, or whereinwhen h is present G is CR₂₄, wherein R₂₄ is selected from H and Me.

In one preferred aspect G is selected from —CH₂—, —CHEt-, —CHMe- and—CMe₂—, or wherein when h is present G is selected from —CH— and —CMe-.

In one preferred aspect G is selected from —CH₂—, —CHMe- and —CMe₂—, orwherein when h is present G is selected from —CH— and —CMe-.

n

As discussed herein n is 0, 1 or 2. Preferably n is 1. In onealternative preferred aspect, n is 0.

D

As discussed herein each D is independently selected from O, NR₂₆ andCR₂₇R₂₈, wherein each R₂₆ is independently selected from H andhydrocarbyl; and each R₂₇ and R₂₈ is independently selected from H, —OH,hydrocarbyl, —CN, —NO₂, and halogens.

Preferably each D is independently selected CR₂₇R₂₈, wherein each R₂₇and R₂₈ is independently selected from H, —OH, hydrocarbyl, —CN, —NO₂,and halogens.

In one preferred aspect, each D is independently selected CR₂₇R₂₈,wherein each R₂₇ and R₂₈ is independently selected from H, OH, C1-6alkoxy and C1-6 alkyl. In one preferred aspect, each D is independentlyselected CR₂₇R₂₈, wherein each R₂₇ and R₂₈ is independently selectedfrom H and C1-6 alkyl.

In one highly preferred aspect, the or each D is independently selectedfrom CHOH, CHOMe, CHOEt, and CH₂. In one highly preferred aspect the oreach D is CH₂.

Halogens

A number of groups defined herein may be selected from halogens. It willbe appreciated that each of these groups may each be independentlyselected from chlorine, fluorine, bromine or iodine. Preferably thehalogen is fluorine.

Preferred Aspects

The present invention provides the following preferred aspects:

-   -   when R₁ is OH and R₃ is of Formula D, (i) at least one of R₄,        R₅, R₆, R₇ and R₈ is independently selected from halocarbyl,        —O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,        —NR₃₂SO₂R₃₃, —CN, and halogens,    -   when R₁ is OH and R₃ is of Formula D, (ii) two or more of R₄,        R₅, R₆, R₇ and R₈ together form a ring    -   two or more of R₄, R₅, R₆, R₇ and R₈ together form a ring    -   when R₁ is OH and R₃ is of Formula D, (iii) at least three of        R₄, R₅, R₆, R₇ and R₈ are independently selected from —OH,        hydrocarbyl, —O-hydrocarbyl, halocarbyl, —O-halocarbyl, —O-acyl,        —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR_(3o)R₃₁, —NR₃₂SO₂R₃₃, —CN, —NO₂,        and halogens    -   at least three of R₄, R₅, R₆, R₇ and R₈ are independently        selected from —OH, hydrocarbyl, —O-hydrocarbyl, halocarbyl,        —O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,        —NR₃₂SO₂R₃₃, —CN, —NO₂, and halogens.    -   —SO₂-hydrocarbyl is a —SO₂—C1-6 alkyl group    -   —SO₂-hydrocarbyl is —SO₂-Me

Other Substituents

The compound of the present invention or for use in the invention mayhave substituents other than those of formula I. By way of example,these other substituents may be one or more of: one or more sulphamategroup(s), one or more halo groups, one or more O groups, one or morehydroxy groups, one or more amino groups, one or more sulphur containinggroup(s), one or more hydrocarbyl group(s)—such as an oxyhydrocarbylgroup.

Composition

As described above according to one aspect of the present invention,there is provided a pharmaceutical composition comprising (a) (i) acompound as defined herein, or (ii) a composition as defined herein, and(b) a pharmaceutically acceptable carrier, diluent, excipient oradjuvant.

In accordance with the present invention the composition of the presentinvention may comprise more than one biological response modifier.

The term biological response modifier (“BRM”) includes cytokines, immunemodulators, growth factors, haematopoiesis regulating factors, colonystimulating factors, chemotactic, haemolytic and thrombolytic factors,cell surface receptors, ligands, leukocyte adhesion molecules,monoclonal antibodies, preventative and therapeutic vaccines, hormones,extracellular matrix components, fibronectin, etc.

BRMs may play a role in modulating the immune and inflammatory responsein disorders. Examples of BRMs include: Tumour Necrosis Factor (TNF),granulocyte colony stimulating factor, erythropoietin, insulin-likegrowth factor (IGF), epidermal growth factor (EGF), transforming growthfactor (TGF), platelet-derived growth factor (PDGF), interferons (IFNs),interleukins, tissue plasminogen activators, P-, E- or L-Selectins,ICAM-1, VCAM, Selectins, addressins etc.

Preferably, the biological response modifier is a cytokine.

A cytokine is a molecule—often a soluble protein—that allows immunecells to communicate with each other. These molecules exert theirbiological functions through specific receptors expressed on the surfaceof target cells. Binding of the receptors triggers the release of acascade of biochemical signals which profoundly affect the behaviour ofthe cell bearing the receptor (Poole, S 1995 TibTech 13: 81-82). Manycytokines and their receptors have been identified at the molecularlevel (Paul and Sedar 1994, Cell 76: 241-251) and make suitablemolecules of therapeutic value as well as therapeutic targets in theirown right.

More details on cytokines can be found in Molecular Biology andBiotechnology (Pub. VCH, Ed. Meyers, 1995, pages 202, 203, 394, 390,475, 790). Examples of cytokines include: interleukins (IL)—such asIL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11,IL-12, IL-19; Tumour Necrosis Factor (TNF)—such as TNF-α; Interferonalpha, beta and gamma; TGF-β.

For the present invention, preferably the cytokine is tumour necrosisfactor (TNF).

More preferably the cytokine is TNF-α.

TNF is a cytokine produced by macrophages and lymphocytes which mediatesinflammatory and immunopathological responses. TNF has been implicatedin the progression of diseases which include but are not limited toimmunomodulation disorder, infection, cell proliferation, angiogenesis(neovascularisation), tumour metastasis, apoptosis, sepsis, andendotoxaemia.

The necrotising action of TNF in vivo mainly relates to capillaryinjury. TNF causes necrosis not only in tumour tissue but also ingranulation tissue. It causes morphological changes in growth inhibitionof and cytoxicity against cultured vascular endothelial cells (Harankaet al 1987 Ciba Found Symp 131: 140-153).

For the preferred aspect of the present invention, the TNF may be anytype of TNF—such as TNF-α, TNF-β, including derivatives or mixturesthereof.

Teachings on TNF may be found in the art—such as WO-A-98/08870 andWO-A-98/13348.

The TNF can be prepared chemically or it can be extracted from sources.Preferably, the TNF is prepared by use of recombinant DNA techniques.

With this aspect of the present invention the compositions of thepresent invention are more potent in vivo than the compounds alone orTNF alone. Moreover, in some aspects the combination of compounds andTNF is more potent than one would expect from the potency of thecompound alone i.e. this is a synergistic relationship between them.

In addition, the present invention contemplates the composition of thepresent invention further comprising an inducer of the biologicalresponse modifier—such as in vivo inducer of the biological responsemodifier.

In accordance with the present invention, the components of thecomposition can be added in admixture, simultaneously or sequentially.Furthermore, in accordance with the present invention it may be possibleto form at least a part of the composition in situ (such as in vivo) byinducing the expression of—or increasing the expression of—one of thecomponents. For example, it may be possible to induce the expressionof—or increase the expression of—the biological response modifier, suchas TNF. By way of example, it may be possible to induce the expressionof—or increase the expression of—TNF by adding bacteriallipopolysaccharide (LPS) and muramyl dipeptide (MDP). In this regard,bacterial LPS and MDP in combination can stimulate TNF production frommurine spleen cells in vitro and tumour regression in vivo (Fuks et alBiull Eksp Biol Med 1987 104: 497-499).

In the method of treatment, the subject is preferably a mammal, morepreferably a human. For some applications, preferably the human is awoman.

The present invention also covers novel intermediates that are useful toprepare the compounds of the present invention. For example, the presentinvention covers novel alcohol precursors for the compounds. By way offurther example, the present invention covers bis protected precursorsfor the compounds. Examples of each of these precursors are presentedherein. The present invention also encompasses a process comprising eachor both of those precursors for the synthesis of the compounds of thepresent invention.

Steroid Sulphatase

Steroid sulphatase—which is sometimes referred to as steroid sulphataseor steryl sulphatase or “STS” for short—hydrolyses several sulphatedsteroids, such as oestrone sulphate, dehydroepiandrosterone sulphate andcholesterol sulphate. STS has been allocated the enzyme number EC3.1.6.2.

STS has been cloned and expressed. For example see Stein et al (J. Biol.Chem. 264:13865-13872 (1989)) and Yen et al (Cell 49:443-454(1987)).

STS is an enzyme that has been implicated in a number of diseaseconditions.

By way of example, workers have found that a total deficiency in STSproduces ichthyosis. According to some workers, STS deficiency is fairlyprevalent in Japan. The same workers (Sakura et al, J Inherit Metab Dis1997 November; 20(6):807-10) have also reported that allergicdiseases—such as bronchial asthma, allergic rhinitis, or atopicdermatitis—may be associated with a steroid sulphatase deficiency.

In addition to disease states being brought on through a total lack ofSTS activity, an increased level of STS activity may also bring aboutdisease conditions. By way of example, and as indicated above, there isstrong evidence to support a role of STS in breast cancer growth andmetastasis.

STS has also been implicated in other disease conditions. By way ofexample, Le Roy et al (Behav Genet 1999 March; 29(2):131-6) havedetermined that there may be a genetic correlation between steroidsulphatase concentration and initiation of attack behaviour in mice. Theauthors conclude that sulphatation of steroids may be the prime mover ofa complex network, including genes shown to be implicated in aggressionby mutagenesis.

STS Inhibition

It is believed that some disease conditions associated with STS activityare due to conversion of a nonactive, sulphated oestrone to an active,nonsulphated oestrone. In disease conditions associated with STSactivity, it would be desirable to inhibit STS activity.

Here, the term “inhibit” includes reduce and/or eliminate and/or maskand/or prevent the detrimental action of STS.

STS Inhibitor

In accordance with the present invention, the compound of the presentinvention is capable of acting as an STS inhibitor.

Here, the term “inhibitor” as used herein with respect to the compoundof the present invention means a compound that can inhibit STSactivity—such as reduce and/or eliminate and/or mask and/or prevent thedetrimental action of STS. The STS inhibitor may act as an antagonist.

The ability of compounds to inhibit oestrone sulphatase activity can beassessed using either intact JEG3 choriocarcinoma cells or placentalmicrosomes. In addition, an animal model may be used. Details onsuitable Assay Protocols are presented in following sections. It is tobe noted that other assays could be used to determine STS activity andthus STS inhibition. For example, reference may also be made to theteachings of WO-A-99/50453.

In one aspect, for some applications, the compound is furthercharacterised by the feature that if the sulphamate group were to besubstituted by a sulphate group to form a sulphate derivative, then thesulphate derivative would be hydrolysable by an enzyme having steroidsulphatase (E.C. 3.1.6.2) activity—i.e. when incubated with steroidsulphatase EC 3.1.6.2 at pH 7.4 and 37° C.

In one preferred embodiment, if the sulphamate group of the compoundwere to be replaced with a sulphate group to form a sulphate compoundthen that sulphate compound would be hydrolysable by an enzyme havingsteroid sulphatase (E.C. 3.1.6.2) activity and would yield a Km value ofless than 200 mmolar, preferably less than 150 mmolar, preferably lessthan 100 mmolar, preferably less than 75 mmolar, preferably less than 50mmolar, when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and37° C.

In a preferred embodiment, the compound of the present invention is nothydrolysable by an enzyme having steroid sulphatase (E.C. 3.1.6.2)activity.

For some applications, preferably the compound of the present inventionhas at least about a 100 fold selectivity to a desired target (e.g.STS), preferably at least about a 150 fold selectivity to the desiredtarget, preferably at least about a 200 fold selectivity to the desiredtarget, preferably at least about a 250 fold selectivity to the desiredtarget, preferably at least about a 300 fold selectivity to the desiredtarget, preferably at least about a 350 fold selectivity to the desiredtarget.

It is to be noted that the compound of the present invention may haveother beneficial properties in addition to or in the alternative to itsability to inhibit STS activity.

Assay for Determining STS Activity Using Cancer Cells (Protocol 1)

Inhibition of Steroid Sulphatase Activity in JEG3 Cells

Steroid sulphatase activity is measured in vitro using intact JEG3choriocarcinoma cells. This cell line may be used to study the controlof human breast cancer cell growth. It possesses significant steroidsulphatase activity (Boivin et al., J. Med. Chem., 2000, 43: 4465-4478)and is available in from the American Type Culture Collection (ATCC).

Cells are maintained in Minimal Essential Medium (MEM) (FlowLaboratories, Irvine, Scotland) containing 20 mM HEPES, 5% foetal bovineserum, 2 mM glutamine, non-essential amino acids and 0.075% sodiumbicarbonate. Up to 30 replicate 25 cm2 tissue culture flasks are seededwith approximately 1×10⁵ cells/flask using the above medium. Cells aregrown to 80% confluency and the medium is changed every third day.

Intact monolayers of JEG3 cells in triplicate 25 cm² tissue cultureflasks are washed with Earle's Balanced Salt Solution (EBSS from ICNFlow, High Wycombe, U.K.) and incubated for 3-4 hours at 37° C. with 5pmol (7×10⁵ dpm) [6,7-3H]oestrone-3-sulphate (specific activity 60Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) in serum-freeMEM (2.5 ml) together with oestrone-3-sulphamate (11 concentrations: 0;1 fM; 0.01 pM; 0.1 pM; 1 pM; 0.01 nM; 0.1 nM; 1 nM; 0.01 mM; 0.1 mM; 1mM). After incubation each flask is cooled and the medium (1 ml) ispipetted into separate tubes containing [14C]oestrone (7×103 dpm)(specific activity 97 Ci/mmol from Amersham International RadiochemicalCentre, Amersham, U.K.). The mixture is shaken thoroughly for 30 secondswith toluene (5 ml). Experiments have shown that >90% [14C] oestrone and<0.1% [3H]oestrone-3-sulphate is removed from the aqueous phase by thistreatment. A portion (2 ml) of the organic phase is removed, evaporatedand the 3H and 14C content of the residue determined by scintillationspectrometry. The mass of oestrone-3-sulphate hydrolysed was calculatedfrom the 3H counts obtained (corrected for the volumes of the medium andorganic phase used, and for recovery of [14C] oestrone added) and thespecific activity of the substrate. Each batch of experiments includesincubations of microsomes prepared from a sulphatase-positive humanplacenta (positive control) and flasks without cells (to assess apparentnon-enzymatic hydrolysis of the substrate). The number of cell nucleiper flask is determined using a Coulter Counter after treating the cellmonolayers with Zaponin. One flask in each batch is used to assess cellmembrane status and viability using the Trypan Blue exclusion method(Phillips, H. J. (1973) In: Tissue culture and applications, [eds:Kruse, D. F. & Patterson, M. K.]; pp. 406-408; Academic Press, NewYork).

Results for steroid sulphatase activity are expressed as the mean±1 S.D.of the total product (oestrone+oestradiol) formed during the incubationperiod (3-4 hours) calculated for 106 cells and, for values showingstatistical significance, as a percentage reduction (inhibition) overincubations containing no oestrone-3-sulphamate. Unpaired Student'st-test was used to test the statistical significance of results.

Assay for Determining STS Activity Using Placental Microsomes (Protocol2)

Inhibition of Steroid Sulphatase Activity in Placental Microsomes

Sulphatase-positive human placenta from normal term pregnancies arethoroughly minced with scissors and washed once with cold phosphatebuffer (pH 7.4, 50 mM) then re-suspended in cold phosphate buffer (5ml/g tissue). Homogenisation is accomplished with an Ultra-Turraxhomogeniser, using three 10 second bursts separated by 2 minute coolingperiods in ice. Nuclei and cell debris are removed by centrifuging (4°C.) at 2000 g for 30 minutes and portions (2 ml) of the supernatant arestored at 20° C. The protein concentration of the supernatants isdetermined by the method of Bradford (Anal. Biochem., 72, 248-254(1976)).

Incubations (1 ml) are carried out using a protein concentration of 100mg/ml, substrate concentration of 20 mM [6,7-3H]oestrone-3-sulphate(specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass.,U.S.A.) and an incubation time of 20 minutes at 37° C. If necessaryeight concentrations of compounds are employed: 0 (i.e. control); 0.05mM; 0.1 mM; 0.2 mM; 0.4 mM; 0.6 mM; 0.8 mM; 1.0 mM. After incubationeach sample is cooled and the medium (1 ml) was pipetted into separatetubes containing [14C]oestrone (7×103 dpm) (specific activity 97 Ci/mmolfrom Amersham International Radiochemical Centre, Amersham, U.K.). Themixture is shaken thoroughly for 30 seconds with toluene (5 ml).Experiments have shown that >90% [14C]oestrone and <0.1%[3H]oestrone-3-sulphate is removed from the aqueous phase by thistreatment. A portion (2 ml) of the organic phase was removed, evaporatedand the 3H and 14C content of the residue determined by scintillationspectrometry. The mass of oestrone-3-sulphate hydrolysed is calculatedfrom the 3H counts obtained (corrected for the volumes of the medium andorganic phase used, and for recovery of [14C]oestrone added) and thespecific activity of the substrate.

Animal Assay Model for Determining STS Activity (Protocol 3)

Inhibition of Oestrone Sulphatase Activity in Vivo

The compounds of the present invention may be studied using an animalmodel, in particular in ovariectomised rats. In this model compoundswhich are oestrogenic stimulate uterine growth.

The compound (0.1 mg/Kg/day for five days) is administered orally torats with another group of animals receiving vehicle only (propyleneglycol). At the end of the study samples of liver tissue were obtainedand oestrone sulphatase activity assayed using 3H oestrone sulphate asthe substrate as previously described (see PCT/GB95/02638).

Animal Assay Model for determining Oestrogenic Activity (Protocol 4)

The compounds of the present invention may be studied using an animalmodel, in particular in ovariectomised rats. In this model, compoundswhich are oestrogenic stimulate uterine growth.

The compound (0.1 mg/Kg/day for five days) was administered orally torats with another group of animals receiving vehicle only (propyleneglycol). At the end of the study uteri were obtained and weighed withthe results being expressed as uterine weight/whole body weight x 100.

Compounds having no significant effect on uterine growth are notoestrogenic.

Biotechnological Assays for Determining STS Activity (Protocol 5)

The ability of compounds to inhibit oestrone sulphatase activity canalso be assessed using amino acid sequences or nucleotide sequencesencoding STS, or active fragments, derivatives, homologues or variantsthereof in, for example, high-through put screens. Such assays andmethods for their practice are taught in WO 03/045925 which isincorporated herein by reference.

In one preferred aspect, the present invention relates to a method ofidentifying agents that selectively modulate STS, which compounds havethe formula (I).

Therapy

The compounds of the present invention may be used as therapeuticagents—i.e. in therapy applications.

The term “therapy” includes curative effects, alleviation effects, andprophylactic effects. The therapy may be on humans or animals,preferably female animals.

Pharmaceutical Compositions

In one aspect, the present invention provides a pharmaceuticalcomposition, which comprises a compound according to the presentinvention and optionally a pharmaceutically acceptable carrier, diluentor excipient (including combinations thereof).

The pharmaceutical compositions may be for human or animal usage inhuman and veterinary medicine and will typically comprise any one ormore of a pharmaceutically acceptable diluent, carrier, or excipient.Acceptable carriers or diluents for therapeutic use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).The choice of pharmaceutical carrier, excipient or diluent can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as—or in addition to—the carrier, excipient or diluent anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s),solubilising agent(s).

Preservatives, stabilisers, dyes and even flavouring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

There may be different composition/formulation requirements dependent onthe different delivery systems. By way of example, the pharmaceuticalcomposition of the present invention may be formulated to be deliveredusing a mini-pump or by a mucosal route, for example, as a nasal sprayor aerosol for inhalation or ingestable solution, or parenterally inwhich the composition is formulated by an injectable form, for delivery,by, for example, an intravenous, intramuscular or subcutaneous route.Alternatively, the formulation may be designed to be delivered by bothroutes.

Where the agent is to be delivered mucosally through thegastrointestinal mucosa, it should be able to remain stable duringtransit though the gastrointestinal tract; for example, it should beresistant to proteolytic degradation, stable at acid pH and resistant tothe detergent effects of bile.

Where appropriate, the pharmaceutical compositions can be administeredby inhalation, in the form of a suppository or pessary, topically in theform of a lotion, solution, cream, ointment or dusting powder, by use ofa skin patch, orally in the form of tablets containing excipients suchas starch or lactose, or in capsules or ovules either alone or inadmixture with excipients, or in the form of elixirs, solutions orsuspensions containing flavouring or colouring agents, or they can beinjected parenterally, for example intravenously, intramuscularly orsubcutaneously. For parenteral administration, the compositions may bebest used in the form of a sterile aqueous solution which may containother substances, for example enough salts or monosaccharides to makethe solution isotonic with blood. For buccal or sublingualadministration the compositions may be administered in the form oftablets or lozenges which can be formulated in a conventional manner.

Combination Pharmaceutical

The compound of the present invention may be used in combination withone or more other active agents, such as one or more otherpharmaceutically active agents.

By way of example, the compounds of the present invention may be used incombination with other STS inhibitors and/or other inhibitors such as anaromatase inhibitor (such as for example, 4-hydroxyandrostenedione(4-OHA)) and/or steroids—such as the naturally occurring neurosteroidsdehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS)and/or other structurally similar organic compounds. Examples of otherSTS inhibitors may be found in the above references. By way of example,STS inhibitors for use in the present invention include EMATE, andeither or both of the 2-ethyl and 2-methoxy 17-deoxy compounds that areanalogous to compound 5 presented herein.

In addition, or in the alternative, the compound of the presentinvention may be used in combination with a biological responsemodifier.

The term biological response modifier (“BRM”) includes cytokines, immunemodulators, growth factors, haematopoiesis regulating factors, colonystimulating factors, chemotactic, haemolytic and thrombolytic factors,cell surface receptors, ligands, leukocyte adhesion molecules,monoclonal antibodies, preventative and therapeutic vaccines, hormones,extracellular matrix components, fibronectin, etc. For someapplications, preferably, the biological response modifier is acytokine. Examples of cytokines include: interleukins (IL)—such as IL-1,IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12,IL-19; Tumour Necrosis Factor (TNF)—such as TNF-α; Interferon alpha,beta and gamma; TGF-β. For some applications, preferably the cytokine istumour necrosis factor (TNF). For some applications, the TNF may be anytype of TNF—such as TNF-α, TNF-β, including derivatives or mixturesthereof. More preferably the cytokine is TNF-α. Teachings on TNF may befound in the art—such as WO-A-98/08870 and WO-A-98/13348.

Administration

Typically, a physician will determine the actual dosage which will bemost suitable for an individual subject and it will vary with the age,weight and response of the particular patient. The dosages below areexemplary of the average case. There can, of course, be individualinstances where higher or lower dosage ranges are merited.

The compositions of the present invention may be administered by directinjection. The composition may be formulated for parenteral, mucosal,intramuscular, intravenous, subcutaneous, intraocular or transdermaladministration. Depending upon the need, the agent may be administeredat a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10mg/kg, more preferably from 0.1 to 1 mg/kg body weight.

By way of further example, the agents of the present invention may beadministered in accordance with a regimen of 1 to 4 times per day,preferably once or twice per day. The specific dose level and frequencyof dosage for any particular patient may be varied and will depend upona variety of factors including the activity of the specific compoundemployed, the metabolic stability and length of action of that compound,the age, body weight, general health, sex, diet, mode and time ofadministration, rate of excretion, drug combination, the severity of theparticular condition, and the host undergoing therapy.

Aside from the typical modes of delivery—indicated above—the term“administered” also includes delivery by techniques such as lipidmediated transfection, liposomes, immunoliposomes, lipofectin, cationicfacial amphiphiles (CFAs) and combinations thereof. The routes for suchdelivery mechanisms include but are not limited to mucosal, nasal, oral,parenteral, gastrointestinal, topical, or sublingual routes.

The term “administered” includes but is not limited to delivery by amucosal route, for example, as a nasal spray or aerosol for inhalationor as an ingestable solution; a parenteral route where delivery is by aninjectable form, such as, for example, an intravenous, intramuscular orsubcutaneous route.

Thus, for pharmaceutical administration, the STS inhibitors of thepresent invention can be formulated in any suitable manner utilisingconventional pharmaceutical formulating techniques and pharmaceuticalcarriers, adjuvants, excipients, diluents etc. and usually forparenteral administration. Approximate effective dose rates may be inthe range from 1 to 1000 mg/day, such as from 10 to 900 mg/day or evenfrom 100 to 800 mg/day depending on the individual activities of thecompounds in question and for a patient of average (70 Kg) bodyweight.More usual dosage rates for the preferred and more active compounds willbe in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day,most preferably from 200 to 250 mg/day. They may be given in single doseregimes, split dose regimes and/or in multiple dose regimes lasting overseveral days. For oral administration they may be formulated in tablets,capsules, solution or suspension containing from 100 to 500 mg ofcompound per unit dose. Alternatively and preferably the compounds willbe formulated for parenteral administration in a suitable parenterallyadministrable carrier and providing single daily dosage rates in therange 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250mg. Such effective daily doses will, however, vary depending on inherentactivity of the active ingredient and on the bodyweight of the patient,such variations being within the skill and judgment of the physician.

Cell Cycling

The compounds of the present invention may be useful in the method oftreatment of a cell cycling disorder.

As discussed in “Molecular Cell Biology” 3rd Ed. Lodish at al. pages177-181 different eukaryotic cells can grow and divide at quitedifferent rates. Yeast cells, for example, can divide every 120 min.,and the first divisions of fertilised eggs in the embryonic cells of seaurchins and insects take only 1530 min. because one large pre-existingcell is subdivided. However, most growing plant and animal cells take10-20 hours to double in number, and some duplicate at a much slowerrate. Many cells in adults, such as nerve cells and striated musclecells, do not divide at all; others, like the fibroblasts that assist inhealing wounds, grow on demand but are otherwise quiescent.

Still, every eukaryotic cell that divides must be ready to donate equalgenetic material to two daughter cells. DNA synthesis in eukaryotes doesnot occur throughout the cell division cycle but is restricted to a partof it before cell division.

The relationship between eukaryotic DNA synthesis and cell division hasbeen thoroughly analysed in cultures of mammalian cells that were allcapable of growth and division. In contrast to bacteria, it was found,eukaryotic cells spend only a part of their time in DNA synthesis, andit is completed hours before cell division (mitosis). Thus a gap of timeoccurs after DNA synthesis and before cell division; another gap wasfound to occur after division and before the next round of DNAsynthesis. This analysis led to the conclusion that the eukaryotic cellcycle consists of an M (mitotic) phase, a G₁ phase (the first gap), theS (DNA synthesis) phase, a G₂ phase (the second gap), and back to M. Thephases between mitoses (G₁, S, and G₂) are known collectively as theinterphase.

Many nondividing cells in tissues (for example, all quiescentfibroblasts) suspend the cycle after mitosis and just prior to DNAsynthesis; such “resting” cells are said to have exited from the cellcycle and to be in the G₀ state.

It is possible to identify cells when they are in one of the threeinterphase stages of the cell cycle, by using a fluorescence-activatedcell sorter (FACS) to measure their relative DNA content: a cell that isin G₁ (before DNA synthesis) has a defined amount x of DNA; during S(DNA replication), it has between x and 2x; and when in G₂ (or M), ithas 2x of DNA.

The Stages of Mitosis and Cytokinesis in an Animal Cell are as Follows

(a) Interphase. The G₂ stage of interphase immediately precedes thebeginning of mitosis. Chromosomal DNA has been replicated and bound toprotein during the S phase, but chromosomes are not yet seen as distinctstructures. The nucleolus is the only nuclear substructure that isvisible under light microscope. In a diploid cell before DNA replicationthere are two morphologic chromosomes of each type, and the cell is saidto be 2n. In G₂, after DNA replication, the cell is 4n. There are fourcopies of each chromosomal DNA. Since the sister chromosomes have notyet separated from each other, they are called sister chromatids.

b) Early prophase. Centrioles, each with a newly formed daughtercentriole, begin moving toward opposite poles of the cell; thechromosomes can be seen as long threads. The nuclear membrane begins todisaggregate into small vesicles.

(c) Middle and late prophase. Chromosome condensation is completed; eachvisible chromosome structure is composed of two chromatids held togetherat their centromeres. Each chromatid contains one of the two newlyreplicated daughter DNA molecules. The microtubular spindle begins toradiate from the regions just adjacent to the centrioles, which aremoving closer to their poles. Some spindle fibres reach from pole topole; most go to chromatids and attach at kinetochores.

(d) Metaphase. The chromosomes move toward the equator of the cell,where they become aligned in the equatorial plane. The sister chromatidshave not yet separated.

(e) Anaphase. The two sister chromatids separate into independentchromosomes. Each contains a centromere that is linked by a spindlefibre to one pole, to which it moves. Thus one copy of each chromosomeis donated to each daughter cell. Simultaneously, the cell elongates, asdo the pole-to-pole spindles. Cytokinesis begins as the cleavage furrowstarts to form.

(f) Telophase. New membranes form around the daughter nuclei; thechromosomes uncoil and become less distinct, the nucleolus becomesvisible again, and the nuclear membrane forms around each daughternucleus. Cytokinesis is nearly complete, and the spindle disappears asthe microtubules and other fibres depolymerise. Throughout mitosis the“daughter” centriole at each pole grows until it is full-length. Attelophase the duplication of each of the original centrioles iscompleted, and new daughter centrioles will be generated during the nextinterphase.

(g) Interphase. Upon the completion of cytokinesis, the cell enters theG₁ phase of the cell cycle and proceeds again around the cycle.

It will be appreciated that cell cycling is an extremely important cellprocess. Deviations from normal cell cycling can result in a number ofmedical disorders. Increased and/or unrestricted cell cycling may resultin cancer. Reduced cell cycling may result in degenerative conditions.Use of the compound of the present invention may provide a means totreat such disorders and conditions.

Thus, the compound of the present invention may be suitable for use inthe treatment of cell cycling disorders such as cancers, includinghormone dependent and hormone independent cancers.

In addition, the compound of the present invention may be suitable forthe treatment of cancers such as breast cancer, ovarian cancer,endometrial cancer, sarcomas, melanomas, prostate cancer, pancreaticcancer etc. and other solid tumours.

For some applications, cell cycling is inhibited and/or prevented and/orarrested, preferably wherein cell cycling is prevented and/or arrested.In one aspect cell cycling may be inhibited and/or prevented and/orarrested in the G₂/M phase. In one aspect cell cycling may beirreversibly prevented and/or inhibited and/or arrested, preferablywherein cell cycling is irreversibly prevented and/or arrested.

By the term “irreversibly prevented and/or inhibited and/or arrested” itis meant after application of a compound of the present invention, onremoval of the compound the effects of the compound, namely preventionand/or inhibition and/or arrest of cell cycling, are still observable.More particularly by the term “irreversibly prevented and/or inhibitedand/or arrested” it is meant that when assayed in accordance with thecell cycling assay protocol presented herein, cells treated with acompound of interest show less growth after Stage 2 of the protocol Ithan control cells. Details on this protocol are presented below.

Thus, the present invention provides compounds which: cause inhibitionof growth of oestrogen receptor positive (ER+) and ER negative (ER−)breast cancer cells in vitro by preventing and/or inhibiting and/orarresting cell cycling; and/or cause regression of nitroso-methyl urea(NMU)-induced mammary tumours in intact animals (i.e. notovariectomised), and/or prevent and/or inhibit and/or arrest cellcycling in cancer cells; and/or act in vivo by preventing and/orinhibiting and/or arresting cell cycling and/or act as a cell cyclingagonist.

Cell Cycling Assay (Protocol 7)

Procedure

Stage 1

MCF-7 breast cancer cells are seeded into multi-well culture plates at adensity of 105 cells/well. Cells were allowed to attach and grown untilabout 30% confluent when they are treated as follows:

Control—no treatment

Compound of Interest (COI) 20 μM

Cells are grown for 6 days in growth medium containing the COI withchanges of medium/COI every 3 days. At the end of this period cellnumbers were counted using a Coulter cell counter.

Stage 2

After treatment of cells for a 6-day period with the COI cells arere-seeded at a density of 10⁴ cells/well. No further treatments areadded. Cells are allowed to continue to grow for a further 6 days in thepresence of growth medium. At the end of this period cell numbers areagain counted.

Cancer

As indicated, the compounds of the present invention may be useful inthe treatment of a cell cycling disorder. A particular cell cyclingdisorder is cancer.

Cancer remains a major cause of mortality in most Western countries.Cancer therapies developed so far have included blocking the action orsynthesis of hormones to inhibit the growth of hormone-dependenttumours. However, more aggressive chemotherapy is currently employed forthe treatment of hormone-independent tumours.

Hence, the development of a pharmaceutical for anti-cancer treatment ofhormone dependent and/or hormone independent tumours, yet lacking someor all of the side-effects associated with chemotherapy, would representa major therapeutic advance.

It is known that oestrogens undergo a number of hydroxylation andconjugation reactions after their synthesis. Until recently it wasthought that such reactions were part of a metabolic process thatultimately rendered oestrogens water soluble and enhanced theirelimination from the body. It is now evident that some hydroxymetabolites (e.g. 2-hydroxy and 16alpha-hydroxy) and conjugates (e.g.oestrone sulphate, E1S) are important in determining some of the complexactions that oestrogens have in the body.

Workers have investigated the formation of 2- and 16-hydroxylatedoestrogens in relation to conditions that alter the risk of breastcancer. There is now evidence that factors which increase 2-hydroxylaseactivity are associated with a reduced cancer risk, while thoseincreasing 16alpha-hydroxylation may enhance the risk of breast cancer.Further interest in the biological role of estrogen metabolites has beenstimulated by the growing body of evidence that 2-methoxyoestradiol isan endogenous metabolite with anti-mitotic properties. 2-MeOE2 is formedfrom 2-hydroxy estradiol (2—OHE2) by catechol estrogen methyltransferase, an enzyme that is widely distributed throughout the body.

Workers have shown that in vivo 2-MeOE2 inhibits the growth of tumoursarising from the subcutaneous injection of Meth A sarcoma, B16 melanomaor MDA-MB-435 estrogen receptor negative (ER−) breast cancer cells. Italso inhibits endothelial cell proliferation and migration, and in vitroangiogenesis. It was suggested that the ability of 2-MeOE2 to inhibittumour growth in vivo may be due to its ability to inhibittumour-induced angiogenesis rather than direct inhibition of theproliferation of tumour cells.

The mechanism by which 2-MeOE2 exerts its potent anti-mitogenic andanti-angiogenic effects is still being elucidated. There is evidencethat at high concentrations it can inhibit microtubule polymerisationand act as a weak inhibitor of colchicine binding to tubulin. Recently,however, at concentrations that block mitosis, tubulin filaments incells were not found to be depolymerised but to have an identicalmorphology to that seen after taxol treatment. It is possible,therefore, that like taxol, a drug that is used for breast and ovarianbreast cancer therapy, 2-MeOE2 acts by stabilising microtubule dynamics.

While the identification of 2-MeOE2 as a new therapy for cancerrepresents an important advance, the bioavailability of orallyadministered oestrogens is poor. Furthermore, they can undergo extensivemetabolism during their first pass through the liver. As part of aresearch programme to develop a steroid sulphatase inhibitor for breastcancer therapy, oestrone-3—O-sulphamate (EMATE) was identified as apotent active site-directed inhibitor. Unexpectedly, EMATE proved topossess potent oestrogenic properties with its oral uterotrophicactivity in rats being a 100-times higher than that of estradiol. Itsenhanced oestrogenicity is thought to result from its absorption by redblood cells (rbcs) which protects it from inactivation during itspassage through the liver and which act as a reservoir for its slowrelease for a prolonged period of time. A number of A-ring modifiedanalogues were synthesised and tested, including2-methoxyoestrone-3-O-sulphamate. While this compound was equipotentwith EMATE as a steroid sulphatase inhibitor, it was devoid ofoestrogenicity.

We believe that the compound of the present invention provides a meansfor the treatment of cancers and, especially, breast cancer.

In addition or in the alternative the compound of the present inventionmay be useful in the blocking the growth of cancers including leukaemiasand solid tumours such as breast, endometrium, prostate, ovary andpancreatic tumours.

Therapy Concerning Oestrogen

We believe that some of the compounds of the present invention may beuseful in the control of oestrogen levels in the body—in particular infemales. Thus, some of the compounds may be useful as providing a meansof fertility control—such as an oral contraceptive tablet, pill,solution or lozenge. Alternatively, the compound could be in the form ofan implant or as a patch.

Thus, the compounds of the present invention may be useful in treatinghormonal conditions associated with oestrogen.

In addition or in the alternative the compound of the present inventionmay be useful in treating hormonal conditions in addition to thoseassociated with oestrogen. Hence, the compound of the present inventionmay also be capable of affecting hormonal activity and may also becapable of affecting an immune response.

Neurodegenerative Diseases

We believe that some of the compounds of the present invention may beuseful in the treatment of Neurodegenerative diseases, and similarconditions.

By way of example, it is believed that STS inhibitors may be useful inthe enhancing the memory function of patients suffering from illnessessuch as amnesia, head injuries, Alzheimer's disease, epileptic dementia,presenile dementia, post traumatic dementia, senile dementia, vasculardementia and post-stroke dementia or individuals otherwise seekingmemory enhancement.

TH1

We believe that some of the compounds of the present invention may beuseful in TH1 implications.

By way of example, it is believed that the presence of STS inhibitorswithin the macrophage or other antigen presenting cells may lead to adecreased ability of sensitised T cells to mount a TH1 (high IL-2, IFNγlow IL-4) response. The normal regulatory influence of other steroidssuch as glucocorticoids would therefore predominate.

Inflammatory Conditions

We believe that some of the compounds of the present invention may beuseful in treating inflammatory conditions—such as conditions associatedwith any one or more of: s autoimmunity, including for example,rheumatoid arthritis, type I and II diabetes, systemic lupuserythematosus, multiple sclerosis, myasthenia gravis, thyroiditis,vasculitis, ulcerative colitis and Crohn's disease, skin disorders e.g.psoriasis and contact dermatitis; graft versus host disease; eczema;asthma and organ rejection following transplantation.

By way of example, it is believed that STS inhibitors may prevent thenormal physiological effect of DHEA or related steroids on immune and/orinflammatory responses.

The compounds of the present invention may be useful in the manufactureof a medicament for revealing an endogenous glucocorticoid-like effect.

Other Therapies

It is also to be understood that the compound/composition of the presentinvention may have other important medical implications.

For example, the compound or composition of the present invention may beuseful in the treatment of the disorders listed in WO-A-99/52890—viz:

In addition, or in the alternative, the compound or composition of thepresent invention may be useful in the treatment of the disorders listedin WO-A-98/05635. For ease of reference, part of that list is nowprovided: cancer, inflammation or inflammatory disease, dermatologicaldisorders, fever, cardiovascular effects, haemorrhage, coagulation andacute phase response, cachexia, anorexia, acute infection, HIVinfection, shock states, graft-versus-host reactions, autoimmunedisease, reperfusion injury, meningitis, migraine and aspirin-dependentanti-thrombosis; tumour growth, invasion and spread, angiogenesis,metastases, malignant, ascites and malignant pleural effusion; cerebralischaemia, ischaemic heart disease, osteoarthritis, rheumatoidarthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration,Alzheimer's disease, atherosclerosis, stroke, vasculitis, Crohn'sdisease and ulcerative colitis; periodontitis, gingivitis; psoriasis,atopic dermatitis, chronic ulcers, epidermolysis bullosa; cornealulceration, retinopathy and surgical wound healing; rhinitis, allergicconjunctivitis, eczema, anaphylaxis; restenosis, congestive heartfailure, endometriosis, atherosclerosis or endosclerosis.

In addition, or in the alternative, the compound or composition of thepresent invention may be useful in the treatment of disorders listed inWO-A-98/07859. For ease of reference, part of that list is now provided:cytokine and cell proliferation/differentiation activity;immunosuppressant or immunostimulant activity (e.g. for treating immunedeficiency, including infection with human immune deficiency virus;regulation of lymphocyte growth; treating cancer and many autoimmunediseases, and to prevent transplant rejection or induce tumourimmunity); regulation of haematopoiesis, e.g. treatment of myeloid orlymphoid diseases; promoting growth of bone, cartilage, tendon, ligamentand nerve tissue, e.g. for healing wounds, treatment of burns, ulcersand periodontal disease and neurodegeneration; inhibition or activationof follicle-stimulating hormone (modulation of fertility);chemotactic/chemokinetic activity (e.g. for mobilising specific celltypes to sites of injury or infection); haemostatic and thrombolyticactivity (e.g. for treating haemophilia and stroke); antiinflammatoryactivity (for treating e.g. septic shock or Crohn's disease); asantimicrobials; modulators of e.g. metabolism or behaviour; asanalgesics; treating specific deficiency disorders; in treatment of e.g.psoriasis, in human or veterinary medicine.

In addition, or in the alternative, the composition of the presentinvention may be useful in the treatment of disorders listed inWO-A-98/09985. For ease of reference, part of that list is now provided:macrophage inhibitory and/or T cell inhibitory activity and thus,anti-inflammatory activity; anti-immune activity, i.e. inhibitoryeffects against a cellular and/or humoral immune response, including aresponse not associated with inflammation; inhibit the ability ofmacrophages and T cells to adhere to extracellular matrix components andfibronectin, as well as up-regulated fas receptor expression in T cells;inhibit unwanted immune reaction and inflammation including arthritis,including rheumatoid arthritis, inflammation associated withhypersensitivity, allergic reactions, asthma, systemic lupuserythematosus, collagen diseases and other autoimmune diseases,inflammation associated with atherosclerosis, arteriosclerosis,atherosclerotic heart disease, reperfusion injury, cardiac arrest,myocardial infarction, vascular inflammatory disorders, respiratorydistress syndrome or other cardiopulmonary diseases, inflammationassociated with peptic ulcer, ulcerative colitis and other diseases ofthe gastrointestinal tract, hepatic fibrosis, liver cirrhosis or otherhepatic diseases, thyroiditis or other glandular diseases,glomerulonephritis or other renal and urologic diseases, otitis or otheroto-rhino-laryngological diseases, dermatitis or other dermal diseases,periodontal diseases or other dental diseases, orchitis orepididimo-orchitis, infertility, orchidal trauma or other immune-relatedtesticular diseases, placental dysfunction, placental insufficiency,habitual abortion, eclampsia, pre-eclampsia and other immune and/orinflammatory-related gynecological diseases, posterior uveitis,intermediate uveitis, anterior uveitis; conjunctivitis, chorioretinitis,uveoretinitis, optic neuritis, intraocular inflammation, e.g. retinitisor cystoid macular oedema, sympathetic ophthalmia, scleritis, retinitispigmentosa, immune and inflammatory components of degenerative fondusdisease, inflammatory components of ocular trauma, ocular inflammationcaused by infection, proliferative vitreo-retinopathies, acute ischaemicoptic neuropathy, excessive scarring, e.g. following glaucoma filtrationoperation, immune and/or inflammation reaction against ocular implantsand other immune and inflammatory-related ophthalmic diseases,inflammation associated with autoimmune diseases or conditions ordisorders where, both in the central nervous system (CNS) or in anyother organ, immune and/or inflammation suppression would be beneficial,Parkinson's disease, complication and/or side effects from treatment ofParkinson's disease, AIDS-related dementia complex HIV-relatedencephalopathy, Devic's disease, Sydenham chorea, Alzheimer's diseaseand other degenerative diseases, conditions or disorders of the CNS,inflammatory components of stokes, post-polio syndrome, immune andinflammatory components of psychiatric disorders, myelitis,encephalitis, subacute sclerosing pan-encephalitis, encephalomyelitis,acute neuropathy, subacute neuropathy, chronic neuropathy,Guillaim-Barre syndrome, Sydenham chora, myasthenia gravis,pseudo-tumour cerebri, Down's Syndrome, Huntington's disease,amyotrophic lateral sclerosis, inflammatory components of CNScompression or CNS trauma or infections of the CNS, inflammatorycomponents of muscular atrophies and dystrophies, and immune andinflammatory related diseases, conditions or disorders of the centraland peripheral nervous systems, post-traumatic inflammation, septicshock, infectious diseases, inflammatory complications or side effectsof surgery, bone marrow transplantation or other transplantationcomplications and/or side effects, inflammatory and/or immunecomplications and side effects of gene therapy, e.g. due to infectionwith a viral carrier, or inflammation associated with AIDS, to suppressor inhibit a humoral and/or cellular immune response, to treat orameliorate monocyte or leukocyte proliferative diseases, e.g. leukaemia,by reducing the amount of monocytes or lymphocytes, for the preventionand/or treatment of graft rejection in cases of transplantation ofnatural or artificial cells, tissue and organs such as cornea, bonemarrow, organs, lenses, pacemakers, natural or artificial skin tissue.

In addition, or in the alternative, the compound or composition of thepresent invention may be useful in the treatment of the disorders listedselected from endometriosis, uterus fibromyoma, induction ofmono-ovulation (in polycystic ovarian disease [PCOD] patients).induction of multiple follicullar development in (ART patients), pretermlabor/cervical incompetency and recurrent abortion.

Compound Preparation

The compounds of the present invention may be prepared by reacting anappropriate alcohol with a suitable chloride. By way of example, thesulphamate compounds of the present invention may be prepared byreacting an appropriate alcohol with a suitable sulfamoyl chloride, ofthe formula R⁴R⁵NSO₂Cl.

Typical conditions for carrying out the reaction are as follows.

Sodium hydride and a sulfamoyl chloride are added to a stirred solutionof the alcohol in anhydrous dimethyl formamide at 0° C. Subsequently,the reaction is allowed to warm to room temperature whereupon stirringis continued for a further 24 hours. The reaction mixture is poured ontoa cold saturated solution of sodium bicarbonate and the resultingaqueous phase is extracted with dichloromethane. The combined organicextracts are dried over anhydrous MgSO₄. Filtration followed by solventevaporation in vacuo and co-evaporated with toluene affords a cruderesidue which is further purified by flash chromatography.

Preferably, the alcohol is derivatised, as appropriate, prior toreaction with the sulfamoyl chloride. Where necessary, functional groupsin the alcohol may be protected in known manner and the protecting groupor groups removed at the end of the reaction.

Preferably, the sulphamate compounds are prepared according to theteachings of Page et al (1990 Tetrahedron 46; 2059-2068).

Preferred preparations are also presented in the following text.

Summary

In summation, the present invention provides novel compounds for use assteroid sulphatase inhibitors and/or aromatase inhibitors and/ormodulators of apoptosis and/or modulators of cell cycling and/or cellgrowth, and pharmaceutical compositions containing them.

EXAMPLES

The present invention will now be described in further detail by way ofexample only with reference to the accompanying figures in which:

FIG. 1 shows a scheme.

FIG. 2 shows a scheme

The present invention will now be described only by way of example.However, it is to be understood that the examples also present preferredcompounds of the present invention, as well as preferred routes formaking same and useful intermediates in the preparation of same.

Synthesis

Synthetic Routes

Compounds in accordance with the present invention were synthesised inaccordance with the synthetic routes and schemes.

The present invention will now be described only by way of example.However, it is to be understood that the examples also present preferredcompounds of the present invention, as well as preferred routes formaking same and useful intermediates in the preparation of same.

Synthesis of 6-(benzyloxy)-2-benzyl-1,2,3,4-tetrahydroisoquinolines

A solution of 6-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline (1.5 mmol)and the appropriate benzyl bromide (1.8 mmol) in TEA (0.5 mL, 3.6 mmol)and ethanol (2.5 mL) was heated at 130° C. for 90 minutes undermicrowave energy. After addition of water (20 mL) and ethyl acetate (80mL), the organic layer was separated and washed with water, brine, dried(MgSO₄) and concentrated under reduced pressure. The resulting yellowsolid was purified by flash chromatography (hexane/ethyl acetate orDCM/ethyl acetate) to give the desired compound.

6-Benzyloxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline 1

350 mg (65%), colorless oil, R_(f): 0.45 (Hexane/EtOAc 2:1), ¹H NMR (270MHz, CDCl₃) δ 2.75 (2H, t, J 5.9 Hz, H3), 2.90 (2H, t, J 5.9 Hz, CH₂),3.62 (2H, s, CH₂), 3.69 (2H, s, CH₂), 3.83 (3H, s, CH₃O), 5.06 (2H, s,OCH₂), 6.77 (1H, s, ArH), 6.80 (1H, dd, J 8.4 and 2.6 Hz, ArH), 6.85(1H, ddd, J 8.2, 3.4 and 1.2 Hz, ArH), 6.94 (1H, d, J 8.4 Hz, ArH), 7.01(1H, d, J 3.4 Hz, ArH), 7.01-7.05 (1H, m, ArH), 7.28 (1H, t, J 8.2 Hz,ArH), 7.30-7.47 (5H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 29.4 (CH₂),50.4 (CH₂), 55.1 (CH₃O), 55.6 (CH₂), 62.7 (CH₂), 69.9 (OCH₂), 112.6(CH(Ar)), 112.8 (CH(Ar)), 114.2 (CH(Ar)), 114.3 (CH(Ar)), 121.3(CH(Ar)), 127.3 (2×CH(Ar)), 127.4 (C(Ar)), 127.5 (CH(Ar)), 127.8(CH(Ar)), 128.4 (2×CH(Ar)), 129.2 (CH(Ar)), 135.5 (C(Ar)), 137.1(C(Ar))140.1 (C(Ar)), 157.0 (C(Ar)) and 159.6 (C(Ar)). LC/MS (APCI+)t_(r)=2.10 min m/z 360.58 (M⁺+H); MeOH/H₂O) 95/5; HPLC t_(r)=5.70 min(97.9%). (CH3CN/H2O 90/10)

2-Benzyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline 2

0.32 g (59%), white solid: m.p. 97-98° C., R_(f): 0.43 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.71 (4H, m, 2×CH₂), 3.53 (2H, s, CH₂),3.66 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 5.10 (2H, s, OCH₂), 6.50 (1H, s,ArH), 6.61 (1H, s, ArH), 7.25-7.45 (5H, m, ArH). ¹³C NMR (67.5 MHz,CDCl₃) δ 28.7 (CH₂), 50.9 (CH₂), 55.9 (CH₂), 56.1 (CH₃O), 62.9 (CH₂),71.1 (CH₂), 110.1 (CH(Ar)), 114.3 (CH(Ar)), 126.3 (C(Ar)), 127.2(CH(Ar)), 127.4 (CH(Ar)), 127.5 (C(Ar)), 127.8 (CH(Ar)), 128.4 (CH(Ar)),128.6 (CH(Ar)), 129.2 (CH(Ar)), 137.4 (C(Ar)), 138.5 (C(Ar)), 146.7(C(Ar)), 147.9 (C(Ar)). LC/MS (APCI+) t_(r)=1.73 min m/z 360.52 (M⁺+H);MeOH/H₂O 95/5; HPLC t_(r)=5.04 min (100%). (CH₃CN/H₂O 90/10); HRMS(Electrospray) calcd. for C₂₄H₂₅NO₂ (MH⁺), 360.1958 found. 360.1955.

6-Benzyloxy-7-methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline3

0.33 g (57%), white solid: mp=96-97° C., R_(f): 0.43 (EtOAc/Hexane 1:1),¹H NMR (270 MHz, CDCl₃) δ 2.72 (4H, m, 2×CH₂), 3.53 (2H, s, CH₂), 3.61(2H, s, CH₂), 3.81 (3H, s, CH₃O), 3.81 (3H, s, CH₃O), 5.11 (2H, s,OCH₂), 6.51 (1H, s, ArH), 6.63 (1H, s, ArH), 6.88 (2H, dd, J 7.4 and 2.0Hz, ArH), 7.26-7.45 (7H, m, ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 28.7(CH₂), 50.8 (CH₂), 55.3 (CH₂), 55.7 (CH₃O), 56.1 (CH₃O), 62.3 (CH₂),71.2 (OCH₂), 110.1 (CH(Ar)), 113.7 (CH(Ar)), 114.3 (CH(Ar)), 126.3(C(Ar)), 127.3 (CH(Ar)), 127.5 (C(Ar)), 127.8 (CH(Ar)), 127.8 (CH(Ar)),128.6 (CH(Ar)), 130.5 (CH(Ar)), 137.1 (C(Ar)), 146.6 (C(Ar)), 147.7(C(Ar)), 158.8 (C(Ar)). LC/MS (APCI+) t_(r)=1.67 min m/z 390.49 (M⁺+H);MeOH/H₂O 95/5; HPLC t_(r)=4.13 min (95.5%). (CH₃CN/H₂O 90/10); HRMS(Electrospray) calcd. for C₂₄H₂₅NO₂ (MH⁺), 390.2064 found. 390.2065

6-Benzyloxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline4

0.39 g (67%), White solid: mp=71-72° C., R_(f): 0.44 (EtOAc/Hexane 1:1)¹H NMR (270 MHz, CDCl₃) δ 2.64-2.76 (4H, m, 2×CH₂), 3.54 (2H, s, CH₂),3.64 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.81 (3H, s, CH₃O), 5.10 (2H, s,OCH₂), 6.51 (1H, s, ArH), 6.63 (1H, s, ArH), 6.83 (1H, ddd, J 8.2, 2.8and 0.9 Hz, ArH), 6.97 (3H, m, ArH), 7.25-7.45 (5H, m, ArH). ¹³C NMR(67.5 MHz, CDCl₃) δ 28.7 (CH₂), 50.8 (CH₂), 55.3 (CH₃O), 55.9 (CH₂),56.1 (CH₃O), 62.8 (CH₂), 71.2 (OCH₂), 110.1 (CH(Ar)), 112.8 (CH(Ar)),114.3 (CH(Ar)), 114.4 (CH(Ar)), 121.5 (CH(Ar)), 126.3 (C(Ar)), 127.3(CH(Ar)), 127.5 (C(Ar)), 127.8 (CH(Ar)), 128.5 (CH(Ar)), 129.3 (CH(Ar)),137.3 (C(Ar)), 140.2 (C(Ar)), 146.7 (C(Ar)), 148.0 (C(Ar)) and 159.8(C(Ar)). LC/MS (APCI+) t_(r)=1.73 min m/z 390.55 (M⁺+H); (MeOH/H₂O99/1); HPLC t_(r)=3.77 min (99%). (CH₃CN/H₂O 90/10); HRMS (Electrospray)calcd. for C₂₅H₂₇NO₃ (MH⁺), 390.2064 found. 390.2063

6-Benzyloxy-7-methoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline5

0.37 g (63%), white powder, mp=85-86° C., R_(f): 0.37 (EtOAc/Hexane 1:1)¹H NMR (270 MHz, CDCl₃) δ 2.75 (4H, m, 2×CH₂), 3.59 (2H, s, CH₂), 3.70(2H, s, CH₂), 3.81 (3H, s, CH₃O), 3.83 (3H, s, CH₃O), 5.10 (2H, s,OCH₂), 6.51 (1H, s, ArH), 6.61 (1H, s, ArH), 6.87 (1H, dd, J 8.4 Hz and1.0 Hz, ArH), 6.94 (1h, dt, J 7.4 and 1.0 Hz, ArH), 7.21-7.44 (7H, m,ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 28.8 (C4), 50.9 (C3), 55.5 (CH₃O),55.8 (C1), 56.1 (CH₃O), 60.5 (NCH₂Ph), 71.1 (OCH₂Ph), 110.2 (C8), 110.5(Ar), 114.3 (C5), 120.4 (Ar), 126.4 (C8a), 126.6, 127.3 and 127.7 (Ph),127.9 (C4a), 128.1, 128.5 and 137.4 (Ph), 146.5 (C7), 147.9 (C6) and157.9 (Ar). LC/MS (APCI+) t_(r)=1.72 min m/z 390.49 (M⁺+H); MeOH/H₂O95/5; HPLC t_(r)=5.12 min (98.5%). (CH₃CN/H₂O 90/10)

6-Benzyloxy-2-(3,5-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline6

0.36 g (62%), white solid: mp=95-96° C., R_(f): 0.44 (EtOAc/Hexane 1:1)¹H NMR (270 MHz, CDCl₃) δ 2.65-2.77 (4H, m, 2×CH₂), 3.54 (2H, s, CH₂),3.60 (2H, s, CH₂), 3.78 (6H, s, 2×CH₃O), 3.81 (3H, s, CH₃O), 5.10 (2H,s, OCH₂), 6.37 (1H, t, J 2.5 Hz, ArH), 6.51 (1H, s, ArH), 6.56 (2H, d, J2.5 Hz, ArH), 6.62 (1H, s, ArH), 7.27-7.44 (5H, m, ArH). ¹³C NMR (67.5MHz, CDCl₃) δ 28.7 (CH₂), 50.7 (CH₂), 55.4 (2×CH₃O), 55.8 (CH₂), 56.1(CH₃O), 63.0 (CH₂), 71.1 (OCH₂), 99.2 (CH(Ar)), 106.8 (2×CH(Ar)), 110.1(CH(Ar)), 114.2 (CH(Ar)), 126.2 (C(Ar)), 127.4 (CH(Ar)), 127.4 (C(Ar)),127.8 (CH(Ar)), 128.6 (CH(Ar)), 137.4 (C(Ar)), 141.0 (C(Ar)), 146.6(C(Ar)), 147.9 (C(Ar)) and 160.8 (C(Ar)). LC/MS (APCI+) t_(r)=5.54 minm/z 420.39 (M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=3.27 min (99.4%).(CH₃CN/H₂O 90/10); HRMS (Electrospray) calcd. for C₂₆H₃₀NO₄ (MH⁺),420.2169 found. 420.6167

6-Benzyloxy-7-methoxy-2-(3-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline7

0.46 g (82%), a white powder, mp=81-82° C., R_(f): 0.69 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.35 (3H, s, CH₃Ph), 2.69-2.76 (4H, m,2×CH₂), 3.52 (2H, s, CH₂), 3.63 (2H, s, CH₂), 3.81 (3H, s, CH₃O), 5.10(2H, s, OCH₂), 6.51 (1H, s, ArH), 6.62 (1H, s, ArH), 7.07-7.44 (9H, m,ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 21.5 (CH₃), 28.8 (CH₂), 50.9 (CH₂),55.8 (CH₂), 56.2 (CH₃O), 62.9 (CH₂), 71.1 (OCH₂), 110.1 (CH(Ar)), 126.3(C(Ar)), 126.4 (CH(Ar)) and 127.3 (CH(Ar)), 127.5 (C(Ar)), 127.8(CH(Ar)), 128.0 (CH(Ar)), 128.2 (CH(Ar)), 128.6 (CH(Ar)), 130.0(CH(Ar)), 137.4 (C(Ar)), 138.0 (C(Ar)) and 138.4 (C(Ar)), 146.7 (CH(Ar))and 147.9 (CH(Ar)). LC/MS (APCI+) t_(r)=1.89 min m/z 374.62 (M+H);MeOH/H₂O 95/5; HPLC t_(r)=11.26 min (98.7%). (MeOH/H₂O 96/4)

6-Benzyloxy-7-methoxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydroisoquinoline8

0.53 g (78%), white powder, mp=111-112° C., R_(f): 0.70 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.65-2.75 (4H, m, 2×CH₂), 3.54 (2H, s,CH₂), 3.64 (2H, s, CH₂), 3.82 (3H, s, CH₃O), 5.10 (2H, s, OCH₂), 6.51(1H, s, ArH), 6.62 (1H, s, ArH), 6.91 (1H, ddd, J 8.2, 2.5 and 1.0 Hz,ArH), 6.98-7.15 (5H, m, Ar), 7.25-7.45 (8H, m, Ar), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.7 (CH₂), 50.8 (CH₂), 55.8 (CH₂), 56.2 (CH₃O), 62.5 (CH₂),71.1 (OCH₂), 110.1 (CH(Ar)), 114.3 (CH(Ar)), 117.7 (CH(Ar)), 118.3(CH(Ar)), 119.7 (CH(Ar)), 123.2 (CH(Ar)), 124.0 (CH(Ar)), 126.3 (C(Ar)),127.3 (CH(Ar)), 127.4 (C(Ar)), 127.8 (CH(Ar)), 128.6 (CH(Ar)), 129.6(CH(Ar)), 129.8(CH(Ar)), 137.4 (C(Ar)) and 140.7 (C(Ar)), 146.7 (C(Ar)),147.9 (C(Ar)), 157.3 (C(Ar)) and 157.4 (C(Ar)). LC/MS (APCI+) t_(r)=2.09min m/z 452.56 (M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=11.68 min (99.8%).(MeOH/H₂O 96/4)

6-Benzyloxy-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline9

0.64 g (82%), white powder, mp=78-79° C., R_(f): 0.62 (Hexane/EtOAc3:1), ¹H NMR (270 MHz, CDCl₃) δ 1.08 (18H, d, J 6.7 Hz, (CH₃)₂CHSi),1.15-1.30 (3H, m, (CH₃)₂CHSi), 2.64-2.75 (4H, m, 2×CH₂), 3.52 (2H, s,CH₂), 3.60 (2H, s, CH₂), 3.81 (3H, s, CH₃O), 5.10 (2H, s, OCH₂), 6.49(1H, s, ArH), 6.61 (1H, s, ArH), 6.75-6.80 (1H, m, ArH), 6.91-6.96 (2H,m, ArH), 7.16 (1H, t, J 7.7 Hz, ArH), 7.27-7.44 (5H, m, ArH), ¹³C NMR(67.5 MHz, CDCl₃) δ 12.7((CH₃)₂CHSi), 18.0 ((CH₃)₂CHSi), 28.8 (CH₂),50.7 (CH₂), 55.9 (CH₂), 56.1 (CH₃O), 62.7 (CH₂), 71.2 (OCH₂), 110.1(CH(Ar)), 114.3 (CH(Ar)), 118.6 (CH(Ar)), 120.8 (CH(Ar)), 126.4 (C4a),127.4 (CH(Ar)), 127.6 (C(Ar)), 127.8 CH(Ar)), 128.6 (CH(Ar)), 129.2(CH(Ar)), 137.4 (C(Ar)), 140.0 (C(Ar)), 146.6 (C(Ar)), 147.9 (C(Ar)) and156.1 (C(Ar)). LC/MS (APCI+) t_(r)=5.96 min m/z 532.71 (M⁺+H); MeOH/H₂O95/5; HPLC t_(r)=14.56 min (99.25%). (MeOH)

6-Benzyloxy-7-methoxy-2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline10

0.50 g (83%), cream color powder, mp=109-110° C., R_(f): 0.32(Hexane/EtOAc 2:1), ¹H NMR (270 MHz, CDCl₃) δ 2.70-2.74 (2H, m, CH₂)2.76-2.78 (2H, m, CH₂), 3.55 (2H, s, CH₂), 3.75 (2H, s, CH₂), 3.81 (3H,s, CH₃O), 5.09 (2H, s, OCH₂), 6.50 (1H, s, ArH), 6.63 (1H, s, ArH),7.24-7.44 (5H, m, ArH), 7.49 (1H, t, J 7.8 Hz, ArH), 7.74 (1H, d, J 7.8Hz, ArH), 8.12 (1H, d, J 7.8 Hz, ArH), 8.25(1H, s, ArH), ¹³C NMR (67.5MHz, CDCl₃) δ 28.5 (CH₂), 50.8 (CH₂), 55.6 (CH₂), 56.0 (CH₃O), 61.7(CH₂), 71.1 (OCH₂), 109.9 (CH(Ar)), 114.2 (CH(Ar)), 122.3 (CH(Ar)),123.7 (CH(Ar)), 125.9 (C(Ar)), 126.8 (C(Ar)), 127.2 (2×CH(Ar)), 127.7(CH(Ar)), 128.5 (CH(Ar)), 129.2 (CH(Ar)), 135.0 (CH(Ar)), 137.2 (C(Ar)),140.9 (C(Ar)), 146.7 (C(Ar)), 147.9 (C(Ar)) and 148.3 (C(Ar)). LC/MS(APCI+) t_(r)=1.57 min m/z 405.60 (M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=4.12min (99.83%). (CH₃CN/H₂O 95/5)

6-Benzyloxy-7-methoxy-2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline11

0.33 g (83%), yellow powder, mp=78-79° C., R_(f): 0.26 (EtOAc/MeOH20:1), ¹H NMR (270 MHz, CDCl₃) δ 2.64-2.76 (4H, m, 2×CH₂), 3.52 (2H, s,CH₂), 3.64 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 5.08 (2H, s, OCH₂), 6.48(1H, s, ArH), 6.61 (1H, s, ArH), 7.22-7.45 (6H, m, 5×ArH and 1×PyrH),7.77 (1H, ddd, J 7.8, 1.7 and 1.4 Hz, ArH), 8.50 (1H, dd, J 4.8 and 1.7Hz, ArH), 8.57 (1H, d, J 1.4 Hz, ArH), 8.25(1H, s, ArH), ¹³C NMR (67.5MHz, CDCl₃) δ 28.7 (CH₂), 50.9 (CH₂), 55.7 (CH₂), 56.2 (CH₃O), 60.0(CH₂), 71.2 (OCH₂), 110.0 (CH(Ar)), 114.3 (CH(Ar)), 123.5 (CHpyr), 126.1(C(Ar)), 127.0 (C(Ar)), 127.3 (2×CH(Ar)), 127.8 (CH(Ar)), 128.6(CH(Ar)), 134.0 (Cpyr), 136.9 (CHpyr), 137.3 (C(Ar)), 146.8 (C(Ar)),148.0 (C(Ar)), 148.8 (CHpyr) and 150.5 (CHpyr). LC/MS (APCI+) t_(r)=4.73min m/z 361.46 (M⁺+H); MeOH/H₂O 95/5 to 50/50 in 5 min; HPLC t_(r)=5.24min (85.4%). (CH₃CN/H₂O 90:10)

6-Benzyloxy-7-methoxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline12

0.45 g (83%), white powder, mp=73-74° C., R_(f): 0.48 (EtOAc/MeOH 10:1),¹H NMR (270 MHz, CDCl₃) δ 2.76 (4H, s, 2×CH₂), 3.60 (2H, s, CH₂), 3.79(3H, s, CH₃O), 3.81 (2H, s, CH₂), 5.09 (2H, s, OCH₂), 6.49 (1H, s, ArH),6.61 (1H, s, ArH), 7.15 (1H, ddd, =7.4, 4.9 and 1.2 Hz, PyrH), 7.22-7.50(6H, m, 5×ArH and 1×PyrH), 7.64 (11-1, dt, J 7.7 and 1.7 Hz, PyrH), 8.55(1H, ddd, J 4.9 1.7 and 0.9 Hz, PyrH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.8(CH₂), 51.2 (CH₂), 55.9 (CH₂), 56.1 (CH₃O), 64.5 (CH₂), 71.2 (OCH₂),110.1 (CH(Ar)), 114.4 (CH(Ar)), 122.2 (CHpyr), 123.2 (CHpyr), 126.2(C(Ar)), 127.3 (2×CH(Ar)), 127.4 (C(Ar)), 127.8 (CH(Ar)), 128.6(CH(Ar)), 136.6 (CHpyr), 137.4 (C(Ar)), 146.7 (C(Ar)), 148.0 (C(Ar)),149.2 (CHpyr) and 158.9 (Cpyr). LC/MS (APCI+) t_(r)=4.88 min m/z 361.59(M⁺+H); MeOH/H₂O 95/5 to 50/50 in 5 min HPLC t_(r)=5.17 min (98.34%).(CH₃CN/H₂O 90:10).

6-Benzyloxy-7-methoxy-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline13

0.33 g (61%), white powder, mp=125-126° C., R_(f): 0.32 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.65-2.78 (4H, m, 2×CH₂), 3.54 (2H, s, CH₂), 3.65(2H, s, CH₂), 3.81 (3H, s, CH₃O), 5.10 (2H, s, OCH₂), 6.49 (1H, s, ArH),6.63 (1H, s, ArH), 7.26-7.45 (7H, m, 5×ArH and 2×PyrH), 8.54 (2H, dd, J4.5 and 1.5 Hz, PyrH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.7 (CH₂), 51.0(CH₂), 55.9 (CH₂), 56.2 (CH₃O), 61.6 (CH₂), 71.2 (OCH₂), 110.0 (CH(Ar)),114.3 (CH(Ar)), 123.9 (2×CHpyr), 126.0 (C(Ar)), 127.0 (C(Ar)), 127.3(2×CH(Ar)), 127.8 (CH(Ar)), 128.6 (2×CH(Ar)), 137.3 (CH(Ar)), 146.9(C(Ar)), 147.9 (Cpyr), 148.0 (C(Ar)), and 150.0 (2×CHpyr). LC/MS (ES−)t_(r)=1.37 min m/z 359.40 (M⁺+H); MeOH/H₂O 95/5. HPLC t_(r)=5.50 min(99.38%). (CH₃CN/H₂O 90:10)

6-Benzyloxy-7-methoxy-2-(4-methoxyphenethyl)-1,2,3,4-tetrahydroisoquinoline14

250 mg (41%), light yellow powder, mp=88-89° C., R_(f): 0.15(Hexane/EtOAc 1:1), ¹H NMR (270 MHz, CDCl₃) g 2.67-2.89 (8H, m, 4×CH₂),3.62 (2H, s, CH₂), 3.78 (3H, s, OCH₃), 3.84 (3H, s, OCH₃), 5.10 (2H, s,OCH₂) 6.55 (1H, s, ArH), 6.62 (1H, s, ArH), 6.81-6.86 (m, 2H, ArH),7.13-7.16 (2H, m, ArH), 7.25-7.44 (5H, m, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.7 (CH₂), 33.2 (CH₂), 51.1 (CH₂), 55.4 (CH₃O), 55.9 (Cl),56.2 (CH3O), 60.6 (CH₂), 71.2 (CH₂O), 110.1 (CH(Ar)), 113.9 (2×CH(Ar)),114.3 (CH(Ar)), 126.2 (C(Ar)), 127.4 (2×CH(Ar)), 127.8 (CH(Ar)), 128.6(2×CH(Ar)), 129.7 (2×CH(Ar)), 132.5 (C(Ar)), 137.4 (C(Ar)), 146.7(C(Ar)), 148.0 (C(Ar)) and 158.0 (C(Ar)). LC/MS (APCI+) t_(r)=5.58 minm/z 404.56 (M⁺+H); MeOH/H₂O 95/5 to 50/50 in 5 min. HPLC t_(r)=8.18 min(99.9%). (CH₃CN/H₂O 90/10)

6-Benzyloxy-2-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline15

370 mg (75%), white powder, mp=126-127° C., R_(f): 0.13 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.75-2.86 (4H, m, 2×CH₂), 3.72 (2H, s,CH₂), 3.81 (3H, s, CH₃O), 3.92 (3H, s CH₃O), 3.93 (5H, s, CH₂ and CH₃O),5.10 (2H, s, OCH₂), 6.51 (1H, s, ArH), 6.61 (1H, s, ArH), 6.85 (1H, d, J8.4 Hz, ArH), 7.27-7.44 (5H, m, ArH), 7.60 (1H, d, J 2.0 Hz, 1H, ArH),7.74 (1H, dd, J 8.4 and 2.0 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.1(CH₂), 51.0 (CH₂), 55.3 (CH₂), 55.9 (CH₃O), 56.0 (CH₃O), 56.1 (CH₃O),63.6 (CH₂), 71.0 (OCH₂), 109.8 (CH(Ar)), 109.9 (CH(Ar)), 110.3 (CH(Ar)),114.1 (CH(Ar)), 123.1 (CH(Ar)), 125.7 (C(Ar)), 126.6 (C(Ar)), 127.2(2×CH(Ar)), 127.7 (CH(Ar)), 128.5 (2×CH(Ar)), 129.1 (C(Ar)), 137.2(C(Ar)), 146.7 (C(Ar)), 147.9 (C(Ar)), 148.9 (C(Ar)), 153.4 (C(Ar)) and195.1 (CO). LC/MS (ES+) t_(r)=1.28 min m/z 448.42 (M⁺+H); MeOH/H₂O50/50; HPLC t_(r)=5.25 min (99.25%). (CH₃CN/H₂O 90/10)

6-Benzyloxy-7-methoxy-2-(2,3,4-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline16

0.29 g (43%), yellow oil R_(f): 0.35 (Hexane/EtOAc 1:2), ¹H NMR (270MHz, CDCl₃) δ 2.66-2.75 (4H, m, 2×CH₂), 3.56 (2H, s, CH₂), 3.63 (2H, s,CH₂), 3.81 (3H, s, CH₃O), 3.85 (3H, s, CH₃O), 3.88 (3H, s, CH₃O), 5.09(2H, s, OCH₂), 6.52 (1H, s, ArH), 6.62 (1H, s, ArH), 6.65 (1H, d, J 8.6Hz, ArH), 7.08 (1H, d, J 8.6 Hz, ArH), 7.27-7.43 (5H, m, ArH), ¹³C NMR(67.5 MHz, CDCl₃) δ 28.9 (CH₂), 50.7 (CH₂), 55.7 (CH₂), 56.1 (CH₃O),56.2 (CH₃O), 56.4 (CH₂), 60.9 (CH₃O), 61.3 (OCH₃), 71.2 (OCH₂Ph), 107.2(CH(Ar)), 110.3 (CH(Ar)), 114.4 (CH(Ar)), 124.4 (C(Ar)), 125.0 (CH(Ar)),126.5 (C(Ar)), 127.4 (2×CH(Ar)), 127.8 (CH(Ar)), 128.0 (C(Ar)), 128.5(2×CH(Ar)), 137.5 (C(Ar)), 142.4 (C(Ar)), 146.7 (C(Ar)), 148.0 (C(Ar)),152.7 (C(Ar)) and 152.9 (C(Ar)).

6-Benzyloxy-7-methoxy-2-(2,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline17

240 mg (36%), white powder, mp=110-111° C., R_(f): 0.20 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CDCl₃) δ 2.65-2.76 (4H, m, 2×CH₂), 3.58 (2H, s,CH₂), 3.63 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.81 (3H, s, CH₃O), 3.82(3H, s, CH₃O), 3.88 (3H, s, CH₃O), 5.09 (2H, s, OCH₂), 6.52 (1H, s,ArH), 6.53 (1H, s, ArH), 6.61 (1H, s, ArH), 7.00 (1H, s, ArH), 7.27-7.43(5H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.8 (CH₂), 50.6 (CH₂), 55.3(CH₂), 55.9 (CH₂), 56.2 (CH₃O), 56.3 (CH₃O), 56.7 (CH₃O), 56.8 (CH₃O),61.7 (CH₂), 71.2 (OCH₂), 97.9 (CH(Ar)), 110.3 (CH(Ar)), 114.3 (CH(Ar)),114.5 (CH(Ar)), 118.3 (C(Ar)), 126.5 (C(Ar)), 127.4 (2×CH(Ar)), 127.8(CH(Ar)), 127.9 (C(Ar)), 128.5 (2×CH(Ar)), 137.5 (C(Ar)), 143.2 (C(Ar)),146.7 (C(Ar)), 148.0 (C(Ar)), 148.6 (C(Ar)) and 152.2 (C(Ar)). LC/MS(ES+) t_(r)=1.82 min m/z 450.61 (M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=3.02min (98.5%). (CH₃CN/H₂O 90:10)

6-Benzyloxy-7-methoxy-2-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline18

430 mg, (68%), white powder: mp=98-99° C., R_(f): 0.30 (Hexane/EtOAc1:2), ¹1-1 NMR (270 MHz, CDCl₃) δ 2.99-3.16 (4H, br, 2×CH₂), 3.81 (3H,s, CH₃O), 3.87 (5H, s, CH₂ and CH₃O), 3.94 (3H, s, CH₃O), 4.01 (2H, s,CH₂), 5.10 (2H, s, OCH₂), 6.47 (1H, s, ArH), 6.64 (1H, s, ArH), 6.81(1H, d, J 8.2 Hz, ArH), 6.91 (1H, dd, J 8.2 and 1.7 Hz, ArH), 7.26-7.50(6H, m, ArH). LC/MS (ES+) t₄=1.48 min m/z 420.61 (M⁺+H); MeOH/H₂O 95/5;HPLC t_(r)=6.45 min (97.9%). (CH₃CN/H₂O 70:30)

6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline19

520 mg (77%), white powder: mp=144-145° C., R_(f): 0.38 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CDCl₃) δ 2.65-2.78 (4H, m, 2×CH₂), 3.55 (2H, s,CH₂), 3.58 (2H, s, CH₂), 3.82 (3H, s, CH₃O), 3.84 (3H, s, CH₃O), 3.85(6H, s, CH₃O), 5.10 (2H, s, OCH₂), 6.53 (1H, s, ArH), 6.61 (2H, s, ArH),6.63 (1H, s, ArH), 7.27-7.44 (5H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ28.8 (CH₂), 50.7 (CH₂), 56.0 (CH₂), 56.2 (3×CH₃O), 61.0 (CH₃O), 63.1(CH₂), 71.2 (OCH₂), 105.7 (2×CH(Ar)), 110.2 (CH(Ar)), 114.3 (CH(Ar)),126.3 (C(Ar)), 127.3 (2×CH(Ar)), 127.5 (C(Ar)), 127.8 (CH(Ar)), 128.6(2×CH(Ar)), 134.5 (C(Ar)), 136.9 (C(Ar)), 137.4 (C(Ar)), 146.8 (C(Ar)),148.0 (C(Ar)) and 153.2 (2×C(Ar)). LC/MS (ES+) t_(r)=1.36 min m/z 450.61(M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=6.39 min (99.7%). (CH₃CN/H₂O 90:10)

6-Benzyloxy-7-methoxy-2-(2,3-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline20

430 mg (68%), light yellow powder, mp=106-107° C., R_(f): 0.46(Hexane/EtOAc 1:2), ¹H NMR (270 MHz, CDCl₃) δ 2.73 (4H, s, 2×CH₂), 3.57(2H, s, CH₂), 3.71 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.83 (3H, s, CH₃O),3.87 (3H, s, CH₃O), 5.09 (2H, s, OCH₂), 6.51 (1H, s, ArH), 6.61 (1H, s,ArH), 6.84 (1H, dd, J 7.2 and 1.7 Hz, ArH), 7.00-7.08 (2H, m, ArH),7.27-7.44 (5H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 29.0 (CH₂), 51.0(CH₂), 55.7 (CH₂), 55.8 (CH₃O), 56.1 (CH₃O), 56.2 (CH₂), 61.0 (OCH₃),71.2 (OCH₂), 110.1 (CH(Ar)), 111.1 (CH(Ar)), 114.3 (CH(Ar)), 122.6(CH(Ar)), 123.9 (CH(Ar)), 126.4 (C(Ar)), 127.4 (2×CH(Ar)), 127.8(C(Ar)), 128.6 (2×CH(Ar)), 132.4 (C(Ar)), 137.4 (C(Ar)), 146.6 (C(Ar)),147.8 (C(Ar)), 147.9 (C(Ar)) and 152.8 (C(Ar)). LC/MS (APCI) t_(r)=1.58min m/z 418.11(M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=3.13 min (94.3%).(CH₃CN/H₂O 90:10)

6-Benzyloxy-7-methoxy-2-(2,5-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline21

440 mg (70%), yellow powder, mg=103-104° C., R_(f): 0.41 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CDCl₃) δ 2.73-2.75 (4H, m, 2×CH₂), 3.61 (2H, s,CH₂), 3.69 (2H, s, CH₂), 3.76 (3H, s, CH₃O), 3.79 (3H, s, CH₃O), 3.82(3H, s, CH₃O), 5.10 (2H, s, OCH₂Ph), 6.53 (1H, s, ArH), 6.62 (1H, s,ArH), 6.76 (1H, dd, J 8.6 and 2.9 Hz, ArH), 6.81 (1H, d, J 8.6 Hz, ArH),7.06 (1H, d, J 2.9 Hz, ArH), 7.28-7.46 (5H, m, ArH). ¹³C NMR (67.5 MHz,CDCl₃) δ 28.8 (C4), 50.9 (C3), 55.9 (C1), 56.2 (CH₃O), 56.3 (CH₃O), 71.2(OCH₂Ph), 110.2 (CH(Ar)), 111.7 (CH(Ar)), 112.5 (CH(Ar)), 114.3(CH(Ar)), 116.1 (CH(Ar)), 126.4 (C(Ar)), 127.4 (2×CH(Ar)), 127.8(C(Ar)), 127.9 (C(Ar)), 128.0 (C(Ar)), 128.6 (2×CH(Ar)), 137.4 (C(Ar)),146.7 (C(Ar)), 147.9 (C(Ar)), 152.1 (C(Ar)) and 153.7 (C(Ar)). LC/MS(ES+) t_(r)=1.77 min m/z 418.11(M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=3.33min (95.7%). (CH₃CN/H₂O 90:10).

6-Benzyloxy-243-fluorobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline22

336 mg, 80%, colourless solid; mp 77-79.5° C. ¹H NMR (270 MHz; CDCl₃)2.67-2.75 (4H, m, 2×CH₂), 3.53 (2H, s, CH₂), 3.64 (2H, s, CH₂), 3.81(3H, s, OCH₃), 5.10 (2H, s, CH₂Ph), 6.50 (1H, s, CH), 6.61 (1H, s, CH),6.91-6.98 (1H, m, CH), 7.10-7.15 (2H, m, 2×CH), 7.23-7.44 (6H, m, CH and5×CH, phenyl). ¹³C NMR (67.5 MHz; CDCl₃) 28.72 (CH₂), 50.91 (CH₂), 55.78(CH₂), 56.16 (OCH₃), 62.32 (CH₂), 71.17 (CH₂), 110.08 (CH), 114.08 (d,J=21.2 Hz, CH), 114.31 (CH), 115.82 (d, J=21.2 Hz, CH), 124.59 (d, J=2.5Hz, CH), 126.18 (C), 127.27 (C), 127.36 (2×CH), 127.84 (CH), 128.59(2×CH), 129.79 (d, J=8.1 Hz, CH), 137.37 (C), 141.37 (d, J=7.5 Hz, C),146.76 (C), 147.97 (C), 163.07 (d, J=245.6 Hz, C—F). LC/MS (APCI+)t_(r)=5.66 min, m/z 378.52 (M⁺+H). HRMS (ES+) calcd. for C₂₄H₂₅FNO₂(M⁺+H) 378.1864, found 378.1866. HPLC t_(r)=8.63 min (>98%).

A solution of7-methoxy-6-(triisopropylsilyloxy)-1,2,3,4-tetrahydroisoquinoline (0.5g, 1.5 mmol) and the appropriate benzyl bromide (1.8 mmol) in TEA (0.5mL, 3.6 mmol) and ethanol (2.5 mL) was heated at 130C for 90 minutesunder microwave energy. After addition of water (20 mL) and ethylacetate (80 mL), the organic layer was separated and washed with water,brine, dried (MgSO₄) and concentrated under reduced pressure. Theresulting yellow solid was purified by flash chromatography(hexane/ethyl acetate or DCM/ethyl acetate) to give the desiredcompound.

2-(3-Acetoxybenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline23

290 mg (65%), yellow oil, R_(f): 0.20 (Hexane/EtOAc 3:1), 0.66(Hexane/EtOAc 1:1), ¹H NMR (270 MHz, CDCl₃) δ 1.05 (18H, d, J 6.7 Hz,(CH₃)₂CHSi), 1.12-1.30 (3H, m, (CH₃)₂CHSi), 2.60 (3H, s, CH₃CO),2.65-2.76 (4H, m, 2×CH₂), 3.54 (2H, s, CH₂), 3.70 (5H, s, OCH₃ and CH₂),6.42 (1H, s, ArH), 6.58 (1H, s, ArH), 7.42 (1H, t, J 7.7 Hz, ArH), 7.62(1H, dt, J 7.7 and 1.5 Hz, ArH), 7.86 (1H, dt, J 7.7 and 1.5 Hz, ArH),7.95 (1H, t, J 1.5 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 13.0((CH₃)₂CHSi), 18.0 ((CH₃)₂CHSi), 26.9 (CH₃CO), 28.4 (CH₂), 50.9 (CH₂),55.7 (CH₃O), 55.9 (CH₂), 62.5 (CH₂), 110.2 (CH(Ar)), 120.2 (CH(Ar)),126.2 (C(Ar)), 126.9 (C(Ar)), 127.3 (CH(Ar)), 128.7 (CH(Ar)), 129.0(CH(Ar)), 134.1 (CH(Ar)), 137.3 (C(Ar)), 139.1 (C(Ar)), 144.0 (C(Ar)),149.1 (C(Ar)) and 198.5 (CO). LC/MS (APCI+) t_(r)=3.80 min m/z 468.57(M⁺+H); MeOH/H₂O 95/5 to 50/50 in 5 min. HPLC t_(r)=30.53 min (80.9%).(CH₃CN/H₂O 90/10)

2-(3-Cyanobenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline24

329 mg, 82%, yellow oil, ¹H NMR (270 MHz; CDCl₃) 1.07 (18H, d, J =6.7Hz, 6×CH ₃CH), 1.13-1.28 (3H, m, 3×CH), 2.66-2.75 (4H, m, 2×CH₂), 3.51(2H, s, CH₂), 3.67 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 6.42 (1H, s, CH),6.59 (1H, s, CH), 7.42 (1H, t, J=7.7 Hz, CH), 7.56 (1H, dt, J=7.7, 1.5Hz, CH), 7.64 (1H, app d, J=7.7 Hz, CH), 7.70 (1H, brs, CH). ¹³C NMR(100 MHz; CDCl₃) 12.87 (3×CH), 17.98 (6×CH₃), 28.27 (CH₂), 50.84 (CH₂),55.58 (OCH₃), 55.67 (CH₂), 61.83 (CH₂), 110.14 (CH), 112.39 (C), 118.93(C), 120.12 (CH), 125.84 (C), 126.50 (C), 129.13 (CH), 130.91 (CH),132.46 (CH), 133.45 (CH), 140.12 (C), 144.02 (C), 149.08 (C). LC/MS(APCI+) t_(r)=3.85 min, m/z 451.43 (M⁺+H).

2-(4-Cyanobenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline25

123 mg, 92%, yellow oil, ¹H NMR (270 MHz; CDCl₃) 1.07 (18H, d, J=6.7 Hz,6×CH₃), 1.13-1.31 (3H, m, 3×CHSi), 2.66-2.75 (4H, m, 2×CH₂), 3.52 (2H,s, CH₂), 3.70 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 6.41 (1H, s, CH), 6.58(1H, s, CH), 7.51 (2H, ˜d, J=8.2 Hz, 2×CH), 7.61 (2H, ˜d, J=8.4 Hz,2×CH). ¹³C NMR (67.5 MHz; CDCl₃) 12.98 (3×CH), 18.05 (6×CH₃), 28.40(CH₂), 50.97 (CH₂), 55.64 (OCH₃), 55.87 (CH₂), 62.27 (CH₂), 110.20 (CH),111.00 (C), 119.06 (C), 120.21 (CH), 125.95 (C), 126.68 (C), 129.83(2×CH), 132.25 (2×CH), 144.10 (C), 144.38 (C), 149.16 (C). LC/MS (APCI+)t_(r)=3.70 min, m/z 451.43 (M⁺+H).

7-Methoxy-2-(3-nitrobenzyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline26

452 mg, 83%, yellow solid; mp 57.3-58.6° C. ¹H NMR. (270 MHz; CDCl₃)1.07 (18H, d, J=6.7 Hz, 6×CH₃), 1.13-1.28 (3H, m, 3×CHSi), 2.69-2.76(4H, m, 2×CH₂), 3.54 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 3.74 (2H, s,CH₂), 6.42 (1H, s, CH), 6.59 (1H, s, CH), 7.49 (1H, t, J=7.9 Hz, CH),7.75 (1H, d, J=7.7 Hz, CH), 8.12 (1H, ddd, J=8.2, 2.5, 1.1 Hz, CH), 8.25(1H, t, J =1.7 Hz, CH). ¹³C NMR (67.5 MHz; CDCl₃) 12.97 (3×CH), 18.06(6×CH₃), 28.47 (CH₂), 50.97 (CH₂), 55.67 (OCH₃), 55.87 (CH₂), 62.02(CH₂), 110.18 (CH), 120.20 (CH), 122.3-7 (CH), 123.88 (CH), 125.99 (C),126.72 (C), 129.34 (CH), 135.22 (CH), 141.04 (C), 144.05 (C), 148.43(C), 149.14 (C). LC/MS (APCI+) t_(r)=4.76 min, m/z 471.58 (M⁺+H). HRMScalcd. for C₂₆H₃₉N₂O₄Si (M⁺+H) 471.2674, found 471.2667.

2-(3-Cyanobenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline27

322 mg, 78%, yellow oil, ¹H NMR (270 MHz; CDCl₃) 1.08 (18H, d, J=6.7 Hz,6×CH₃), 1.13-1.29 (3H, m, 3×CHSi), 2.66-2.75 (4H, m, 2×CH₂), 3.52 (2H,s, CH₂), 3.62 (2H, s, CH₂), 3.72 (3H, s, OCH₃), 6.43 (1H, s, CH), 6.59(1H, s, CH), 7.23-7.28 (3H, m, 3×CH), 7.40 (1H, s, CH). ¹³C NMR (67.5MHz; CDCl₃) 12.99 (3×CH), 18.06 (6×CH₃), 28.51 (CH₂), 50.92 (CH₂), 55.67(CH₃), 55.89 (CH₂), 62.37 (CH₂), 110.31 (CH), 120.20 (CH), 126.15 (C),127.04 (C), 127.28 (CH), 127.35 (CH), 129.16 (CH), 129.69 (CH), 134.29(C), 140.79 (C), 143.99 (C), 149.09 (C). LC/MS (APCI+) t_(r)=6.75 min,m/z 460.43 (M⁺+H).

7-Methoxy-2-(3-(trifluoromethoxy)benzyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline28

238 mg, 52%, pale blue oil. ¹H NMR (270 MHz; CDCl₃) 1.07 (18H, d, J=6.7Hz, 6×CH₃), 1.14-1.28 (3H, m, 3×CH), 2.65-2.74 (4H, m, 2×CH), 3.53 (2H,s, CH₂), 3.66 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 6.43 (1H, s, CH), 6.58(1H, s, CH), 7.09-7.12 (1H, m, CH), 7.20-7.38 (3H, m, 3×CH). LC/MS (ES+)t_(r)=5.93 min, m/z 510.49 (M⁺+H).

2-(2-Hydroxybenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline29

171 mg, 70%, pale yellow oil, ¹H NMR (270 MHz; CDCl₃) 1.07 (18H, d,J=6.7 Hz, 6×CH₃), 1.15-1.29 (3H, m, 3×CH), 2.79 (4H, brs, 2×CH₂), 3.65(2H, brs, CH₂), 3.72 (3H, s, OCH₃), 3.85 (2H, s, CH₂), 6.43 (1H, s, CH),6.59 (1H, s, CH), 6.76-6.86 (2H, m, 2×CH), 7.01 (1H, dd, J=7.4, 1.5 Hz,CH), 7.15-7.21 (1H, m, CH). LC/MS (ES+) t_(r)=4.66 min, m/z 442.57(M⁺+H).

6-Benzyloxy-2-(4-cyanobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline29A

White powder (0.36 g, 62%), mp=161-162° C., R_(f): 0.41 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.65-2.76 (4H, m, 2×CH₂), 3.53 (2H, s,CH₂), 3.70 (2H, s, CH₂), 3.81 (3H, s, CH₃O), 5.10 (2H, s, CH₂), 6.49(1H, s, ArH), 6.63 (1H, s, ArH), 7.21-7.44 (7H, m, ArH), 7.50 (2H, m,ArH), 7.60 (2H, m, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ 28.7 (CH₂), 51.0(CH₂), 55.8 (CH₂), 56.1 (CH₃O), 62.3 (CH₂), 71.1 (CH₂), 110.0 (CH(Ar)),111.0 (C(Ar)), 114.3 (CH(Ar)), 119.1 (CN), 126.0 (C(Ar)), 127.0 (C(Ar)),127.3(2×CH(Ar)), 127.9 (CH(Ar)), 128.6 (2×CH(Ar)), 129.5 (2×CH(Ar)),132.3 (2CH(Ar)), 137.3 (C(Ar)) and 144.6 (C(Ar)), 146.9 (C(Ar)), 148.1(C(Ar)). LC/MS (APCI+) t_(r)=1.39 min m/z 385.51 (M⁺+H); (MeOH/H₂O95/5). HRMS calcd. for C₂₅H₂₅N₂O₂ (MH⁺), 385.1911 found. 385.1912; HPLCt_(r)=2.71 min (97.7%). (CH₃CN/H₂O 90/10).

6-Benzyloxy-2-(3-hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline30

A solution of6-(benzyloxy)-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline(2.7 g, 5 mmol) in THF (50 mL) was cooled to 0° C. and 1M TBAF/THF (5.5mL, 5.5 mmol) added drop wise. The solution was stirred at 0 C for 1 h30 min and water (20 mL) added as well as EtOAc (80 mL). The organiclayer was washed with water, brine, dried with MgSO₄, filtered andconcentrated under reduced pressure. The resulting solid was washed withhexane, filtered and dried. 1.7 g (90%), white powder, mp=78-79° C.;R_(f): 0.12 (Hexane/EtOAc 3:1), ¹H NMR (270 MHz, CDCl₃) δ 2.63-2.78 (4H,m, 2×CH₂), 3.52 (2H, s, CH₂), 3.58 (2H, s, CH₂), 3.79 (3H, s, CH₃O),5.08 (2H, s, OCH₂), 6.48 (1H, s, ArH), 6.60 (1H, s, ArH), 6.68 (1H, dd,J 8.2 and 2.5 Hz, ArH), 6.82 (1H, d, J 2.5 Hz, ArH), 6.88 (1H, d, J 7.7Hz, ArH), 7.15 (1H, dd, J 8.2 and 7.7 Hz, 1H, ArH), 7.26-7.47 (5H, m,ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 12.7((CH₃)₂CHSi), 18.0 ((CH₃)₂CHSi),28.8 (CH₂), 50.7 (CH₂), 55.9 (CH₂), 56.1 (CH₃O), 62.7 (CH₂), 71.2(OCH₂), 110.1 (CH(Ar)), 114.3 (CH(Ar)), 118.6 (CH(Ar)), 120.8 (CH(Ar)),126.4 (C(Ar)), 127.4 (CH(Ar)), 127.6 (C(Ar)), 127.8 CH(Ar)), 128.6(CH(Ar)), 129.2 (CH(Ar)), 137.4 (C(Ar)), 140.0 (C(Ar)), 146.6 (C(Ar)),147.9 (C(Ar)) and 156.1 (C(Ar)). LC/MS (APCI+) t_(r)=5.12 min m/z 376.59(M⁺+H); MeOH/H₂O 50/50 to 95/5 (5 min); HPLC t_(r)=3.26 min (100%).(CH₃CN/H₂O 90/10)

6-(Benzyloxy)-2-(3-ethoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline31

A mixture of 30 (450 mg, 1.2 mmol), EtI (0.19 mL, 2.4 mmol) and K₂CO₃(207 mg, 1.5 mmol) in EtOH was stirred at rt for 18 hours. Afteraddition of water, the organics were extracted with ethyl acetate, theorganic layer washed with water, brine, dried (MgSO₄), filtered and thesolvents evaporated under reduced pressure. The crude solid was purifiedby flash chromatography (hexane/ethyl acetate 4:1) to give 200 mg (41%)of yellow oil, R_(f): 0.68 (Hexane/EtOAc 1:1), ¹H NMR (270 MHz, CDCl₃) δ1.39 (3H, t, J 6.9 Hz, CH₃), 2.65-2.79 (4H, m, 2×CH₂), 3.54 (2H, s,CH₂), 3.63 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 4.01 (2H, q, J 6.9 Hz,CH₂), 5.09 (2H, s, CH₂), 6.50 (1H, s, ArH), 6.61 (1H, s, ArH), 6.79 (1H,ddd, J 7.9, 2.2 and 1.0 Hz, ArH), 6.93-6.96 (2H, m, ArH), 7.20 (1H, t, J7.9 Hz, 1H, ArH), 7.26-7.44 (5H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ15.0 (CH₃), 28.7 (CH₂), 50.8 (CH₂), 55.8 (CH₂), 56.1 (CH₃O), 62.8 (CH₂),63.4 (CH₂O), 71.2 (CH₂O), 110.1 (CH(Ar)), 113.3 (CH(Ar)), 114.3(CH(Ar)), 115.1 (CH(Ar)), 121.4 (CH(Ar)), 126.3 (C(Ar)), 127.3(2×CH(Ar)), 127.5 (C(Ar)), 127.8 (CH(Ar)), 128.6 (2×CH(Ar)), 129.3(CH(Ar)), 137.4 (C(Ar)), 140.1 (C(Ar)), 146.6 (C(Ar)), 147.9 (C(Ar)) and159.1 (C(Ar)). LC/MS (APCI+) t_(r)=5.68 min m/z 404.59 (M⁺+H); MeOH/H2O50/50 to 95/5 (5 min); HPLC t_(r)=8.80 min (84.7%). (CH₃CN/H₂O 90/10)

6-(Benzyloxy)-2-(3-isopropoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline32

Sodium hydride (48 mg, 1.2 mmol) was added to a solution of 30 (300 mg,0.8 mmol) in THF (10 ml) and the reaction mixture was stirred at rt for20 min. 2-Iodopropane (0.12 ml, 1.2 mmol) was added and the reactionmixture was stirred at rt for 26 h. Further 2-iodopropane (0.36 ml, 3.6mmol) was added and the reaction mixture was heated at 60° C. 24 h. Thesolution was concentrated in vacuo, water was added and the aqueouslayer was extracted with ethyl acetate (3×). The combined organic phaseswere washed with brine, dried (MgSO₄) and concentrated in vacuo.Purification (flashmaster: 50 g, 100% hex-100% EtOAc over 35 min)afforded the title compound (259 mg, 77%) as a colourless oil; ¹H NMR(270 MHz; CDCl₃) 1.31 (6H, d, J=6.2 Hz, 2×CH₃), 2.66-2.75 (4H, m,2×CH₂), 3.54 (2H, s, CH₂), 3.62 (2H, s, CH₂), 3.80 (3H, s, OCH₃), 4.54(1H, septet, J=6.2 Hz, CH), 5.09 (2H, s, CH₂Ph), 6.50 (1H, s, CH), 6.61(1H, s, CH), 6.77-6.81 (1H, m, CH), 6.91-6.94 (2H, m, 2×CH), 7.16-7.47(6H, m, 5×CH, phenyl). ¹³C NMR (67.5 MHz; CDCl₃) 22.18 (CH₃), 28.77(CH₂), 50.80 (CH₂), 55.85 (CH₂), 56.16 (OCH₃), 62.85 (CH₂), 69.75 (CH),71.18 (CH₂), 110.13 (CH), 114.30 (CH), 114.59 (CH), 116.47 (CH), 126.31(C), 127.35 (CH), 127.55 (C), 127.82 (CH), 128.58 (CH), 129.32 (CH),137.40 (C), 140.16 (C), 146.69 (C), 147.91 (C), 158.02 (C). LC/MS(APCI−) t_(r)=7.47 min, m/z 416.35 (M−H)⁻.

3-((6-(Benzyloxy)-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenylacetate 33

A solution of 30 (450 mg, 1.2 mmol), acetic anhydride (0.13 mL, 1.4mmol), TEA (0.2 mL, 1.4 mmol) in CHCl₃ (10 mL) was stirred at rt o/n.After addition of CHCl₃ (50 mL), the organic layer was washed withwater, brine, dried (MgSO₄), filtered and concentrated. The crudeproduct was purified by flash chromatography (hexane/EtOAc 4:1 to 3:1)to give 450 mg (90%) of white powder. mp=94-95° C., R_(f): 0.51(Hexane/EtOAc 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.28 (3H, s, CH3CO),2.65-2.77 (4H, m, 2×CH₂), 3.52 (2H, s, CH₂), 3.65 (2H, s, CH₂), 3.80(3H, s, CH₃O), 5.10 (2H, s, OCH₂), 6.50 (1H, s, ArH), 6.61 (1H, s, ArH),6.98 (1H, ddd, J 7.9 and 2.2 and 1.2 Hz, ArH), 7.13-7.19 (1H, m, ArH),7.21-7.44 (7H, m, ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 21.3 (CH₃CO), 28.7(CH₂), 50.9 (CH₂), 55.8 (CH₂), 56.1 (CH₃O), 62.4 (CH₂), 71.2 (OCH₂),110.1 (CH(Ar)), 114.3 (CH(Ar)), 120.4 (CH(Ar)), 122.0 (CH(Ar)), 126.2(C(Ar)), 126.5 (CH(Ar)), 127.3 (CH(Ar)), 127.4 (C(Ar)), 127.8 (CH(Ar)),128.6 (CH(Ar)), 129.3 (CH(Ar)), 137.4 (C(Ar)), 140.6 (C(Ar)), 146.7(C(Ar)), 147.9 (C(Ar)), 150.8 (C(Ar)) and 169.7 (CO). LC/MS (ES+)t_(r)=5.06 min m/z 418.48 (M⁺+H); MeOH/H₂O 50/50 to 95/5 (5 min) HPLCt_(r)=4.74 min (100%). (CH₃CN/H₂O 90/10)

2-(3-Aminobenzyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline34

6-(Benzyloxy)-7-methoxy-2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline(1.61 g, 4 mmol) was added to a suspension of Raney Nickel (1.5 g of 50%slurry in water, washed 3×5 mL of methanol) in methanol (50 mL). Afterdrop wise addition of hydrazine hydrate (1 mL), the mixture was refluxedfor 30 minute, cooled to RT and filtered through celite. The solvent wasremoved under reduced pressure and the resulting yellow solid wasstirred in diethyl ether, filtered and dried, yielding 1.4 g (93%) of ayellow powder, mp=114-115° C., R_(f): 0.38 (EtOAc/MeOH 10:1), ¹H NMR(270 MHz, CDCl₃) δ 2.68-2.77 (4H, m, 2×CH₂), 3.53 (2H, s, CH₂), 3.58(2H, s, CH₂), 3.81 (3H, s, CH₃O), 5.11 (2H, s, OCH₂), 6.52 (1H, s, ArH),6.59 (1H, dd, J 8.2 and 1.5 Hz, ArH), 6.63 (1H, s, ArH), 6.75-6.78 (2H,m, ArH), 7.12 (1H, t, J 8.0 Hz, 1H, ArH), 7.29-7.45 (5H, m, ArH), ¹³CNMR (67.5 MHz, CDCl₃) δ 28.7 (CH₂), 51.0 (CH₂), 55.9 (CH₂), 56.1,(CH₃O), 63.0 (CH₂), 71.2 (CH₂O), 110.2 (CH(Ar)), 114.0 (CH(Ar)), 114.4(CH(Ar)), 115.7 (CH(Ar)), 119.5 (CH(Ar)), 126.3 (C4a), 127.4 (2×CH(Ar)),127.6 (C8a), 127.9 (CH(Ar)), 128.6 (2×CH(Ar)), 129.2 (CH(Ar)), 137.4(C(Ar)), 139.8 (C(Ar)), 146.6 (C(Ar)), 146.7 (C(Ar)) and 147.9 (C(Ar)).LC/MS (APCI+) t_(r)=1.32 min m/z 375.63 (M⁺+H); MeOH/H2O 50/50 to 95/5(5 min); HPLC t_(r)=6.86 min (98.33%). (CH₃CN/H₂O 90/10)

2-(3-Acetamidobenzyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline35

A solution of3-((6-(benzyloxy)-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)aniline(300 mg, 0.8 mmol), acetic anhydride (0.26 mL, 2.7 mmol), TEA (0.39 mL,2.7 mmol) in CHCl₃ (30 mL) was stirred at RT for 3 h. After addition ofwater, the organic layer was separated, washed water, brine, dried(MgSO4), filtered and concentrated under reduced pressure. 280 mg ofyellow oil was obtained which was flash columned (EtOAc/Hexane 10/1)then re-columned with DCM/EtOAc (2:1 to 1:5) to give 180 mg (54%) of awhite powder. Mp=63-66° C. R_(f): 0.26 (EtOAc/MeOH 20:1), ¹H NMR (270MHz, CDCl₃) δ 2.14 (3H, s, CH₃CO), 2.68-2.75 (4H, m, 2×CH₂), 2.84 (br,1H, NH), 3.52 (2H, s, CH₂), 3.64 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 5.09(2H, s, OCH₂), 6.48 (1H, s, ArH), 6.60 (1H, s, ArH), 7.11 (1H, d, J 7.7Hz, 1H, ArH), 7.24-7.43 (7H, m, ArH), 7.53 (1H, d, J 8.2, ArH). ¹³C NMR(67.5 MHz, CDCl₃) δ 24.7 (CH₃CO), 28.6 (CH₂), 50.9 (CH₂), 55.6 (CH₂),56.1 (CH₃O), 62.5 (CH₂), 71.2 (CH₂O), 110.1 (CH(Ar)), 114.2 (CH(Ar)),118.9 (CH(Ar)), 120.3 (CH(Ar)), 125.1 (CH(Ar)), 126.1 (C(Ar)), 127.1(C(Ar)), 127.3 (2×CH(Ar)), 127.8 (CH(Ar)), 128.6 (2×CH(Ar)), 129.1(CH(Ar)), 137.3 (C(Ar)), 138.0 (C(Ar)), 139.3 (C(Ar)), 146.7 (C(Ar)),147.9 (C(Ar)) and 168.6 (CO). LC/MS (APCI+) t_(r)=4.93 min m/z 417.44(M⁺+H); MeOH/H₂O 95/5 to 50/50 in 5 min; HPLC t_(r)=5.03 min (93.4%).(CH₃CN/H₂O 90:10)

6-(Benzyloxy)-2-(3-methanesulfonylaminobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline36

Mesyl chloride (0.09 mL, 1.2 mmol) was added drop wise to a solution of6-benzyloxy-2-(3-(aminobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline(374 mg, 1 mmol) in pyridine (2 mL). The mixture was stirred for an 18hours at room temperature. After addition of water, the organics wereextracted with ethyl acetate, the organic layer was washed with water,brine, dried (MgSO4), filtered and concentrated. The crude white solidwas purified by flash chromatography (hexane/EtOAc 1:4) to give 260 mg(58%) of white powder. mp=132-133° C., R_(f): 0.44 (EtOAc), ¹H NMR (270MHz, CDCl₃) δ 2.64-2.76 (4H, m, 2×CH₂), 2.97 (3H, s, CH3SO₂), 3.52 (2H,s, CH₂), 3.63 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 5.09 (2H, s, OCH₂), 6.49(1H, s, ArH), 6.61 (1H, s, ArH), 7.12-7.44 (10H, m, ArH, NH). ¹³C NMR(67.5 MHz, CDCl₃) δ 28.7 (CH₂), 39.5 (CH₃SO₂), 50.9 (CH₂), 55.8 (CH₂),56.2 (CH₃O), 62.3 (CH₂), 71.1 (OCH₂), 110.1 (C8), 114.3 (C5), 119.5(CH(Ar)), 121.3 (CH(Ar)), 126.1 (CH(Ar)), 126.2 (C4a), 127.2 (C8a),127.3 (2×CH(Ar)), 127.8 (CH(Ar)), 128.6 (2×CH(Ar)), 129.6 (CH(Ar)),136.9 (C(Ar)), 137.3 (C(Ar)), 140.6 (C(Ar)), 146.8 (C(Ar)), 148.0(C(Ar)). LC/MS (ES+) t_(r)=4.62 min m/z 453.40 (M⁺+H); MeOH/H₂O 50/50 to95/5 (5 min); HPLC t_(r)=5.97 min (100%). (CH₃CN/H₂O 90/10)

2-(3-(Methoxycarbonyl)benzyl)-6-triisopropylsilyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline36A

Purification (flashmaster: 20 g, gradient elution hex/EtOAc) affordedthe title compound (318 mg, 73%) as a colourless oil. ¹H NMR (270 MHz;CDCl₃) 1.06 (18H, d, J=6.7 Hz, 6×CH₃CH), 1.14-1.28 (3H, m, 3×CH),2.68-2.74 (4H, m, 4×CH), 3.52 (2H, s, 2×CH), 3.69 (2H, s, 2×CH), 3.70(3H, s, OCH₃), 3.90 (3H, s, OCH₃), 6.41 (1H,s , CH), 6.57 (1H, brd,J=7.7 Hz, CH), 7.94 (1H, dt, J 7.7, 1.3 Hz, CH), 8.03 (1H, brs, CH). ¹³CNMR (67.5 MHz; CDCl₃) 12.96 (3×CH), 18.05 (6×CH₃), 28.51 (CH₂), 50.89(CH₂), 52.21 (CH₃), 55.66 (CH₃), 55.90 (CH₂), 62.59 (CH₂), 110.27 (CH),120.18 (CH), 126.16 (C), 127.07 (C), 128.52 (CH), 130.24 (C), 130.34(C), 133.88 (CH), 139.01 (C), 143.94 (C), 149.06 (C), 167.31 (C). LC/MS(APCI−) t_(r)=3.76 min, m/z 326.15 (M-Si(iPr)₃-H)⁻.

6-Benzyloxy-2-(3-acetoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline36B

A solution of6-benzyloxy-2-(3-hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline30 (450 mg, 1.2 mmol), acetic anhydride (0.13 mL, 1.4 mmol), TEA (0.2mL, 1.4 mmol) in CHCl₃ (10 mL) was stirred at rt for 18 hours. Afteraddition of CHCl₃ (50 mL), the organic layer was washed with water,brine, dried (MgSO₄), filtered and concentrated. The crude product waspurified by flash chromatography (hexane/EtOAc 4:1 to 3:1) to give awhite powder (450 mg, 90%), mp=94-95° C., R_(f): 0.51 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.28 (3H, s, CH₃), 2.65-2.77 (4H, m,2×CH₂), 3.52 (2H, s, CH₂), 3.65 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 5.10(2H, s, CH₂), 6.50 (1H, s, ArH), 6.61 (1H, s, ArH), 6.98 (1H, ddd, J=7.9and 2.2 and 1.2 Hz, ArH), 7.13-7.19 (1H, m, ArH), 7.21-7.44 (7H, m,ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ 21.3 (CH₃), 28.7 (CH₂), 50.9 (CH₂),55.8 (CH₂), 56.1 (CH₃O), 62.4 (CH₂), 71.2 (CH₂), 110.1 (CH(Ar)), 114.3(CH(Ar)), 120.4 (CH(Ar)), 122.0 (CH(Ar)), 126.2 (C(Ar)), 126.5 (CH(Ar)),127.3 (2×CH(Ar)), 127.4 (C(Ar)), 127.8 (CH(Ar)), 128.6 (2×CH(Ar)), 129.3(CH(Ar)), 137.4 (C(Ar)), 140.6 (C(Ar)), 146.7 (C(Ar)), 147.9 (C(Ar)),150.8 (C(Ar)) and 169.7 (CO). LC/MS (ES+) t_(r)=4.06 min m/z 418.48(M⁺+H); gradient MeOH/H₂O 50/50 to 95/5 (5 min); HPLC t_(r)=4.74 min(100%). (CH₃CN/H₂O 90/10)

Synthesis of 6-hydroxy-2-benzyl-1,2,3,4-tetrahydroisoquinolines

A solution of 6-(benzyloxy)-2-benzyl-1,2,3,4-tetrahydroisoquinoline (1mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C (40mg) and stirred under an atmosphere of hydrogen. The reaction wasmonitored by TLC. Upon completion, the resultant suspension was filteredthrough celite, washed with ethyl acetate and then evaporated underreduced pressure. The crude mixture was purified by flash chromatography(hexane/ethyl acetate) or (DCM/ethyl acetate).

6-Hydroxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline 37

White powder, 205 mg (76%), mp=223-224° C., R_(f): 0.29 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.67-2.78 (4H, m, 2×CH₂), 3.55 (2H, s,CH₂), 3.65 (2H, s, CH₂), 3.76 (3H, s, CH₃O), 6.40 (1H, d, J 2.5 Hz,ArH), 6.51 (1H, dd, J 8.4, 2.5 Hz, ArH), 6.79 (1H, d, J 8.4 Hz, ArH),6.81 (1H, dd, J 8.4 and 2.0 Hz, ArH), 6.93-6.97 (2H, m, ArH), 7.22 (1H,t, J 8.4 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 29.0 (CH₂), 50.6 (CH₂),55.3 (CH₃O), 55.6 (CH₂), 62.8 (CH₂), 113.1 (CH(Ar)), 113.4 (CH(Ar)),114.6 (CH(Ar)), 115.1 (CH(Ar)), 121.8 (CH(Ar)), 126.6 (C(Ar)), 127.8(CH(Ar)), 129.3 (CH(Ar)), 135.6 (C(Ar)), 139.5 (C(Ar)), 154.2 (C(Ar))and 159.7 (C(Ar)). LC/MS (APCI+) t_(r)=4.43 min m/z 270.46 (M⁺+H);MeOH/H2) 95/5; HPLC t_(r)=4.80 min (97.1%). (CH3CN/H2O 90/10)

2-Benzyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline 38

Light yellow powder, 105 mg (39%), mp 134-135° C., R_(f): 0.47 (ethylacetate/hexane 3:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68-2.80 (4H, m, 2×CH₂),3.52 (2H, s, CH₂), 3.66 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 5.49 (1H, br,OH), 6.44 (1H, s, ArH), 6.64 (1H, s, ArH), 7.22-7.40 (5H, m, ArH), ¹³CNMR (67.5 MHz, CDCl₃) δ 28.5 (CH₂), 50.9 (CH₂), 55.8 (CH₂), 56.0 (CH₃O),62.8 (CH₂), 108.8 (CH(Ar)), 114.3 (CH(Ar)), 126.1 (C(Ar)), 127.0(C(Ar)), 127.2 (CH(Ar)), 128.4 (2×CH(Ar)), 129.3 (2×CH(Ar)), 138.4(C(Ar)), 144.0 (C(Ar)) and 144.9 (C(Ar)). LC/MS (APCI+) t_(r)=1.33 minm/z 270.46 (M⁺+H); HPLC t_(r)=3.06 min (97.42%). (CH₃CN/H₂O 90/10); HRMS(Electrospray) calcd. for C₁₇H₁₉NO₂ (MH⁺), 270.1489 found. 270.1488

6-Hydroxy-7-methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline39

Light yellow powder, 180 mg (60%), mp 162-163° C., R_(f): 0.12 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.69-2.78 (4H, m, 2×CH₂),3.49 (2H, s, CH₂), 3.60 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 3.80 (3H, s,CH₃O), 5.41 (1H, br, OH), 6.44 (1H, s, ArH), 6.62 (1H, s, ArH), 6.86(2H, m, ArH), 7.29 (2H, m, ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 27.5 (CH₂),50.3 (CH₂), 55.1 (CH₂), 55.3 (CH₃O), 55.9 (CH₃O), 61.6 (CH₂), 109.1(CH(Ar)) 113.7 (2×CH(Ar)), 114.6 (CH(Ar)), 124.6 (C(Ar)), 126.2 (C(Ar)),128.5 (C(Ar)), 130.9 (2×CH(Ar)), 144.4 (C(Ar)), 145.5 (C(Ar)) and 159.1(C(Ar)). LC/MS (APCI+) t_(r)=1.67 min m/z 300.50 HPLC t_(r)=6.99 min(97.6%). (MeOH/H₂O 99/1); HRMS (Electrospray) calcd. for C₁₈H₂₁NO₃(MH⁺), 300.1594 found. 300.1593.

6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline40

Light yellow powder, 180 mg (60%), mp 161-162° C., R_(f): 0.21 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.67-2.80 (4H, m, 2×CH₂),3.53 (2H, s, CH₂), 3.64 (2H, s, CH₂), 3.79 (6H, s, 2×CH₃O), 5.55 (1H,br, OH), 6.45 (1H, s, ArH), 6.64 (1H, s, ArH), 6.81 (1H, ddd, J 8.1, 2.4and 1.0 Hz, ArH), 6.96 (2H, m, ArH), 7.23 (1H, t, J 8.1 Hz, ArH), ¹³CNMR (67.5 MHz, CDCl₃) δ 28.6 (CH₂), 50.9 (CH₂), 55.3, (CH₃O), 55.9(CH₂), 56.1 (CH₃O), 62.9 (CH₂), 108.9 (CH(Ar)) 112.8 (CH(Ar)), 114.2(CH(Ar)), 114.5 (CH(Ar)), 121.4 (CH(Ar)), 126.2 (C(Ar)), 127.0 (C(Ar)),129.3 (CH(Ar)), 140.2 (C(Ar)), 144.0 (C(Ar)), 145.0 (C(Ar)) and 159.7(C(Ar)). LC/MS (APCI+) t_(r)=1.31 min m/z 300.44 (M⁺+H); (MeOH/H₂O95/5); HPLC t_(r)=2.76 min (97.4%). (CH₃CN/H₂O 90/10); HRMS(Electrospray) calcd. for C₁₈H₂₂NO₃ (MH⁺), 300.1594 found. 300.1591

6-Hydroxy-7-methoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline41

Yellow powder, 190 mg (63%), mp=128-129° C., R_(f): 0.27 (EtOAc/Hexane2:1), ¹H NMR (270 MHz, CDCl₃) δ 2.73-2.82 (4H, m, 2×CH₂), 3.60 (2H, s,CH₂), 3.71 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.83 (3H, s, CH₃O), 5.47(1H, br, OH), 6.46 (1H, s, ArH), 6.63 (1H, s, ArH), 6.87 (1H, d, J 7.9Hz, ArH), 6.94 (1H, dt, J 7.4 and 1.0 Hz, ArH), 7.24 (1H, dt, J 7.4 and1.7 Hz, ArH), 7.43 (1H, dd, J 7.4 and 1.7 Hz, ArH). ¹³C NMR (67.5 MHz,CDCl₃) δ 28.5 (CH₂), 51.0 (CH₂), 55.6 (CH₃O), 55.8 (CH₂), 55.9 (CH₂),56.1 (CH₃O), 108.9 (CH(Ar)), 110.5 (CH(Ar)), 114.3 (CH(Ar)), 114.6 (Ar),120.4 (CH(Ar)), 126.4 (C(Ar)), 127.1 (C(Ar)), 128.1 (CH(Ar)), 130.4(CH(Ar)), 144.0 (C(Ar)), 144.8 (C(Ar)), 157.9 (C(Ar)). LC/MS (APCI+)t_(r)=5.65 min m/z 300.44 (M⁺+H); HPLC t_(r)=4.12 min (94%). (CH₃CN/H₂O90/10)

6-Hydroxy-2-(3,5-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline42

Yellow powder, 285 mg (86%), mp=127-128° C., R_(f): 0.28 (EtOAc/Hexane2:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68-2.78 (4H, m, 2×CH₂), 3.53 (2H, s,CH₂), 3.60 (2H, s, CH₂), 3.78 (6H, s, 2×CH₃O), 3.80 (3H, s, CH₃O), 6.37(1H, t, J 2.4 Hz, ArH), 6.46 (1H, s, ArH), 6.57 (2H, d, J 2.4 Hz, ArH),6.64 (1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.5 (CH₂), 50.9 (CH₂),55.5 (2×CH₃O), 55.8 (CH₂), 56.1 (CH₃O), 62.9 (CH₂), 56.1 (CH₃O), 99.30(CH(Ar)), 106.9 (2×CH(Ar)), 109.0 (CH(Ar)), 114.3 (CH(Ar)), 126.0(C(Ar)), 127.0 (C(Ar)), 144.0 (C(Ar)), 144.8 (C(Ar)) and 160.8 (2×Ar).LC/MS (APCI+) t^(r)=4.48 min m/z 330.42 (M⁺+H); HPLC t_(r)=3.58 min(98.2%). (CH₃CN/H₂O 70/30)

6-Hydroxy-7-methoxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydroisoquinoline43

Yellow powder, 255 mg (71%), mp=139-140° C., R_(f): 0.52 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.67-2.76 (4H, m, 2×CH₂), 3.53 (2H, s,CH₂), 3.64 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 6.45 (1H, s, ArH), 6.64(1H, s, ArH), 6.90 (1H, ddd, J 8.2, and 1.6 Hz, ArH), 6.99-7.15 (5H, m,Ar), 7.28-7.35 (3H, m, Ar), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.5 (CH₂), 50.8(CH₂), 55.7 (CH₂), 56.0 (CH₃O), 62.5 (CH₂), 108.8 (CH(Ar)), 114.2(CH(Ar)), 117.6 (CH(Ar)), 118.8 (CH(Ar)), 119.7 (CH(Ar)), 123.2(CH(Ar)), 124.1 (CH(Ar)), 126.1 (C(Ar)), 127.0 (C(Ar)), 129.6 (CH(Ar)),129.8 (CH(Ar)), 140.7 (C(Ar)), 144.0 (C(Ar)), 144.9 (C(Ar)), 157.3(C(Ar)) and 157.4 (C(Ar)). LC/MS (APCI+) t_(r)=5.40 min m/z 362.47(M⁺+H); HPLC t_(r)=5.14 min (99.8%). (MeOH/H₂O 90/10)

6-Hydroxy-7-methoxy-2-(3-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline 44

Yellow powder, 170 mg (60%), mp=128-129° C., R_(f): 0.53 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.34 (3H, s, CH₃), 2.68-2.78 (4H, m,2×CH₂), 3.52 (2H, s, CH₂), 3.63 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 6.45(1H, s, ArH), 6.64 (1H, s, ArH), 7.06-7.10 (1H, m, ArH), 7.14-7.25 (3H,m, ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 21.5 (CH₃), 28.5 (CH₂), 51.0 (CH₂),55.9 (CH₂), 56.0 (CH₃O), 62.9 (CH₂), 108.9 (CH(Ar)), 114.2 (CH(Ar)),126.2 (C(Ar)), 126.3 (CH(Ar)), 127.0 (C(Ar)), 127.9 (CH(Ar)), 128.2(CH(Ar)), 130.0 (CH(Ar)), 138.0 (C(Ar)), 138.3 (C(Ar)), 144.0 (C(Ar)),144.9 (C(Ar)). LC/MS (APCI+) t_(r)=5.40 min m/z 362.47 (M⁺+H); HPLCt_(r)=5.14 min (99.8%). (MeOH/H₂O 90/10)

6-Hydroxy-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline45

A solution of6-(benzyloxy)-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline(425 mg, 0.8 mmol) in THF (10 mL) and methanol (30 mL) was stirred with10% Pd/C (40 mg) under hydrogen for 30 minutes. After filtration throughcelite and evaporation of the solvents under reduced pressure, theresidual oil was purified by flash chromatography (hexane/ethyl acetate5/1 to 4/1) to give 250 mg (71%) of a yellow oil. R_(f): 0.30(Hexane/EtOAc 3:1), ¹H NMR (270 MHz, CDCl₃) δ 1.09 (18H, d, J 6.7 Hz,(CH₃)₂CHSi), 1.16-1.31 (3H, m, (CH₃)₂CHSi), 2.66-2.77 (4H, m, 2×CH₂),3.52 (2H, s, CH₂), 3.61 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 6.44 (1H, s,ArH), 6.62 (1H, s, ArH), 6.74-6.81 (1H, m, ArH), 6.93-6.96 (2H, m, ArH),7.16 (1H, t, J 7.8 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ12.8((CH₃)₂CHSi), 18.0 ((CH₃)₂CHSi), 28.5 (CH₂), 50.8 (CH₂), 55.8 (CH₂),56.0 (CH₃O), 62.7 (CH₂), 108.9 (CH(Ar)), 114.4 (CH(Ar)), 118.6 (CH(Ar)),120.8 (CH(Ar)), 122.0 (CH(Ar)), 126.2 (C(Ar)), 127.1 (C(Ar)), 129.2(CH(Ar)), 139.9 (C(Ar)), 144.0 (C(Ar)), 145.0 (C(Ar)) and 156.1 (C(Ar)).LC/MS (APCI+) t_(r)=5.96 min m/z 532.71 (M⁺+H); MeOH/H₂O) 95/5; HPLCt_(r)=16.49 min (100%). (CH₃CN/H₂O 90/10)

6-Hydroxy-7-methoxy-2-(4-methoxyphenethyl)-1,2,3,4-tetrahydroisoquinoline46

Yellow powder, 280 mg (90%), mp=170-171° C., R_(f): 0.18 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CDCl₃) δ 2.67-2.88 (8H, m, 4×CH₂), 3.62 (2H, s,CH₂), 3.78 (3H, s, OCH₃), 3.82 (3H, s, OCH₃), 6.50 (1H, s, ArH), 6.63(1H, s, ArH), 6.80-6.85 (m, 2H, ArH), 7.12-7.18 (2H, m, ArH), ¹³C NMR(67.5 MHz, CDCl₃) δ 28.5 (CH₂), 33.1 (CH₂), 51.2 (CH₂), 55.4 (CH₃O),55.9 (CH₂), 56.0 (CH₃O), 60.6 (CH₂), 108.9 (CH(Ar)), 113.9 (2×CH(Ar)),114.4 (CH(Ar)), 125.9 (C(Ar)),126.9 (C(Ar)), 129.7 (2×CH(Ar)), 132.5(C(Ar)), 144.1 (C(Ar)), 145.1 (C(Ar)) and 158.0 (C(Ar)). LC/MS (APCI+)t_(r)=4.57 min m/z 314.49 (M⁺+H); MeOH/H₂O 95/5 to 50/50 in 5 min. HPLCt_(r)=6.99 min (99.03%). (CH₃CN/H₂O 90/10)

6-Hydroxy-7-methoxy-2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline47

Yellow powder, 145 mg (53%), mp=165-166° C., R_(f): 0.26 (EtOAc/MeOH20:1), ¹H NMR (270 MHz, CDCl₃/CD₃COCDl₃ 3:1) δ 2.47-2.58 (4H, m, 2×CH₂),3.23 (2H, s, CH₂), 3.47 (2H, s, CH₂), 3.58 (3H, s, CH₃O), 6.26 (1H, s,ArH), 6.41 (1H, s, ArH), 7.08 (1H, dd, J 7.8 and 4.9 Hz, PyrH), 7.56(1H, dt, J 7.8, 1.7 Hz, PyrH), 8.31 (1H, dd, J 4.9 and 1.7 Hz, PyrH),8.38 (1H, d, J 1.7 Hz, PyrH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCDl₃ 3:1) δ28.3 (CH₂), 50.7 (CH₂), 55.6 (CH₂), 55.8 (CH₃O), 59.8 (CH₂), 108.9(CH(Ar)), 114.4 (CH(Ar)), 123.4 (CHpyr), 125.3 (C(Ar)), 126.4 (C(Ar)),134.0 (Cpyr), 136.7 (CHpyr), 144.3 (C(Ar)), 145.3 (C(Ar)), 148.4 (CHpyr)and 150.1 (CHpyr). LC/MS (APCI+) t_(r)=1.04 min m/z 271.30 (M⁺+H);MeOH/H₂O 95/5. HPLC t_(r)=4.26 min (97.33%). (CH₃CN/H₂O 90:10)

6-Hydroxy-7-methoxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline48

Yellow powder, 185 mg (69%), mp=137-138° C., R_(f): 0.39 (EtOAc/MeOH10:1), ¹H NMR (270 MHz, CDCl₃) δ 2.72-2.826 (4H, m, 2×CH₂), 3.59 (2H, s,CH₂), 3.79 (3H, s, CH₃O), 3.82 (2H, s, CH₂), 5.78 (1H, br, OH), 6.45(1H, s, ArH), 6.64 (1H, s, ArH), 7.17 (1H, ddd, =7.4, 4.9 and 1.0 Hz,PyrH), 7.50 (1H, d, J 7.7 Hz, PyrH), 7.66 (1H, dt, J 7.7 and 2.0 Hz,PyrH), 8.56 (1H, ddd, J 4.9 2.0 and 1.0 Hz, PyrH), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.6 (CH₂), 51.2 (CH₂), 55.9 (CH₂), 56.0 (CH₃O), 64.4 (CH₂),108.8 (CH(Ar)), 114.3 (CH(Ar)), 122.2 (CHpyr), 123.2 (CHpyr), 126.0(C(Ar)), 127.0 (C(Ar)), 136.6 (CHpyr), 144.1 (C(Ar)), 145.0 (C(Ar)),149.2 (CHpyr) and 159.0 (Cpyr). LC/MS (APCI+) t_(r)=3.34 min m/z 271.44(M⁺+H); MeOH/H₂O 95/5 to 50/50 in 5 min; HPLC t_(r)=4.32 min (99.5%).(CH₃ CN/H₂O 90:10)

6-Hydroxy-7-methoxy-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline49

Yellow powder, 73 mg (54%), R_(f): 0.30 (EtOAc/MeOH 10:1), ¹H NMR (270MHz, CDCl₃) δ 2.67-2.82 (4H, m, 2×CH₂), 3.52 (2H, s, CH₂), 3.66 (2H, s,CH₂), 3.80 (3H, s, CH₃O), 5.77 (1H, br, OH), 6.44 (1H, s, ArH), 6.66(1H, s, ArH), 7.33 (2H, dd, J 4.6 and 1.5 Hz, 2×PyrH), 8.54 (2H, dd, J4.6 and 1.5 Hz, PyrH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.5 (CH₂), 51.1(CH₂), 55.9 (CH₂), 56.0 (CH₃O), 61.6 (CH₂), 108.8 (CH(Ar)), 114.4(CH(Ar)), 123.9 (2×CHpyr), 125.7 (C(Ar)), 126.8 (C(Ar)), 144.3 (C(Ar)),145.1 (Cpyr), 148.0 (C(Ar)), and 149.9 (2×CHpyr). LC/MS (ES−) t_(r)=1.04min m/z 269.34 (M⁺+H); MeOH/H₂O 95/5. HPLC t_(r)=4.31 min (98.64%).(CH₃CN/H₂O 90:10)

6-Hydroxy-7-methoxy-2-(3-acetamidobenzyl)-1,2,3,4-tetrahydroisoquinoline50

Light yellow solid, 165 mg (51, R_(f): 0.42 (EtOAc/MeOH 10:1), ¹H NMR(270 MHz, CD₃COCD₃) δ 2.06 (3H, s, CH₃CO), 2.64-2.73 (4H, m, 2×CH₂),3.43 (2H, s, CH₂), 3.59 (2H, s, CH₂), 3.75 (3H, s, CH₃O), 6.55 (2H, s,ArH), 7.03 (1H, d, J 7.4 Hz, 1H, ArH), 7.23 (1H, dd, J 8.2 and 7.4 Hz,ArH), 7.60 (1H, s, ArH), 7.63 (1H, d, J 8.2 Hz, ArH), 9.13 (1H, br, NH),¹³C NMR (67.5 MHz, CD₃COCD₃) δ 23.5 (CH₃CO), 28.7 (CH₂), 51.1 (CH₂),55.4 (CH₃O), 55.6 (CH₂), 62.6 (CH₂), 109.6 (CH(Ar)), 114.7 (CH(Ar)),117.8 (CH(Ar)), 119.2 (CH(Ar)), 123.5 (CH(Ar)), 125.9 (C(Ar)), 126.6(C(Ar)), 128.5 (CH(Ar)), 139.8 (2×C(Ar)), 145.0 (C(Ar)), 145.9 (C(Ar))and 168.1 (CO). LC/MS (APCI+) t_(r)=3.78 min m/z 327.54 (M⁺+H); MeOH/H₂O50/50 to 95/5 (5 min; LC/MS (ES−) t_(r)=3.78 min m/z 325.33 (M−H)⁻;MeOH/H₂O 50/50 to 95/5 (5 min); HPLC t_(r)=4.32 min (96.9%) (CH₃CN/H₂O90/10)

6-Hydroxy-7-methoxy-2-(3-acetoxybenzyl)-1,2,3,4-tetrahydroisoquinoline51

Light yellow powder, 165 mg (50%), mp=120-122° C., R_(f): 0.37(Hexane/EtOAc 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.28 (3H, s, CH₃),2.67-2.80 (4H, m, 2×CH₂), 3.51 (2H, s, CH₂), 3.66 (2H, s, CH₂), 3.80(3H, s, CH₃O), 5.46 (1H, s, OH), 6.45 (1H, s, ArH), 6.64 (1H, s, ArH),6.98 (1H, ddd, J 7.9 and 2.2 and 1.2 Hz, ArH), 7.14 (1H, t, J 1.7 Hz,ArH), 7.21-7.26 (1H, m, ArH), 7.32 (1H, t, J 7.7 Hz, ArH), ¹³C NMR (67.5MHz, CDCl₃) δ 21.3 (CH₃), 28.6 (CH₂), 51.0 (CH₂), 55.8 (CH₂), 56.1(CH₃O), 62.4 (CH₂), 108.9 (CH(Ar)), 114.3 (CH(Ar)), 120.4 (CH(Ar)),122.0 (CH(Ar)), 126.1 (C(Ar)), 126.5 (CH(Ar)), 127.0 (C(Ar)), 129.3(CH(Ar)), 140.6 (C(Ar)), 144.0 (C7), 144.9 (C(Ar)), 150.8 (C(Ar)) and169.7 (CO). LC/MS (ES+) t_(r)=3.88 min m/z 328.36 (Ar+H); MeOH/H₂O 50/50to 95/5 (5 min); HPLC t_(r)=4.41 min (93.1%). (CH₃CN/H₂O 90/10).

6-Hydroxy-7-methoxy-2-(3-methanesulfonylaminobenzyl)-1,2,3,4-tetrahydroisoquinoline52

Yellow powder, 340 mg (94%), mp=99-101° C., R_(f): 0.27 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.66-2.78 (4H, m, 2×CH₂), 2.98 (3H, s, CH₃), 3.51(2H, s, CH₂), 3.64 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 6.44 (1H, s, ArH),6.62 (1H, s, ArH), 7.14-7.33 (5H, m, ArH, NH), ¹³C NMR (67.5 MHz, CDCl₃)δ 28.5 (CH₂), 39.5 (CH₃), 50.9 (CH₂), 55.8 (CH₂), 56.1 (CH₃O), 62.3(CH₂), 108.9 (CH(Ar)), 114.4 (CH(Ar)), 119.5 (CH(Ar)), 121.4 (CH(Ar)),125.9 (C(Ar)), 126.1 (CH(Ar)), 126.9 (C(Ar)), 129.7 (CH(Ar)), 136.9(C(Ar)), 140.5 (C(Ar)), 144.1 (C(Ar)), 145.0 (C(Ar)). LC/MS (ES−)t_(r)=1.09 min m/z 361.54 (M⁻−H); MeOH/H₂O 95/5; HPLC t_(r)=3.91 min(99.57%). (CH₃CN/H₂O 90/10)

2-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline53

Yellow powder, 140 mg (39%), mp=149-150° C., R_(f): 0.21 (Hexane/EtOAc1:5), ¹H NMR (270 MHz, CDCl₃) δ 2.80-2.88 (4H, m, 2×CH₂), 3.71 (2g s,CH₂), 3.80 (3H, s, CH₃O), 3.91 (3H, s CH₃O), 3.93 (5H, s, CH₃O and CH₂),4.98 (11-1, br, OH), 6.46 (1H, s, 6.64 (1H, s, ArH), 6.85 (1H, d, J 8.4Hz, ArH), 7.61(1H, d, J 2.0 Hz, ArH), 7.74 (1H, dd, J 8.4 and 2.0 Hz,ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.2 (CH₂), 51.3 (CH₂), 55.7 (CH₂),56.0 (CH₃O), 56.1 (CH₃O), 56.2 (CH₃O), 64.1 (CH₂), 108.7 (CH(Ar)), 110.0(CH(Ar)), 110.5 (CH(Ar)), 114.3 (CH(Ar)), 123.2 (CH(Ar)), 125.6 (C(Ar)),126.7 (C(Ar)), 129.3 (C(Ar)), 144.1 (C(Ar)), 145.0 (C(Ar)), 149.0(C(Ar)), 153.5 (C(Ar)) and 195.5 (CO).

6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline54

Yellow powder, 215 mg (60%), mp=170-171° C., R_(f): 0.27 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.66-2.81 (4H, m, 2×CH₂), 3.53 (2H, s, CH₂), 3.59(2H, s, CH₂), 3.81 (3H, s, CH₃O), 3.84 (3H, s, CH₃O), 3.85 (6H, s,CH₃O), 5.49 (1H, br, OH), 6.48 (1H, s, ArH), 6.62 (2H, s, ArH), 6.66(1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.6 (CH₂), 50.8 (CH₂), 56.0(CH₂), 56.1 (CH₃O), 56.2 (2×CH₃O), 61.0 (CH₃O), 63.0 (CH₂), 105.7(2×CH(Ar)), 108.9 (CH(Ar)), 114.3 (CH(Ar)), 126.1 (C(Ar)), 127.1(C(Ar)), 127.8 (CH(Ar)), 134.4 (C(Ar)), 136.9 (C(Ar)), 144.1 (C(Ar)),145.0 (C(Ar)) and 153.2 (2×C(Ar)). LC/MS (APCI−) t_(r)=1.15 min m/z358.15 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.66 min (98.3%). (CH₃CN/H₂O90:10)

6-Hydroxy-7-methoxy-2-(2,5-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline55

Yellow powder, 158 mg (48%), mp=104-105° C., R_(f): 0.30 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.71-2.80 (4H, m, 2×CH₂), 3.60 (2H, s, CH₂), 3.68(2H, s, CH₂), 3.75 (3H, s, CH₃O), 3.79 (3H, s, CH₃O), 3.80 (3H, s,CH₃O), 5.60 (1H, br, OH), 6.47 (1H, s, ArH), 6.63 (1H, s, ArH),6.73-6.82 (2H, m, ArH), 7.06 (1H, d, J 2.9 Hz, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.6 (CH₂), 50.9 (CH₂), 55.7 (CH₂), 55.8 (CH₃O), 55.9 (CH₂),56.1 (CH₃O), 56.3 (CH₃O), 108.9 (CH(Ar)), 111.7 (CH(Ar)), 112.5 CH(Ar)),114.3 (CH(Ar)), 116.1 (CH(Ar)), 126.5 (C(Ar)), 127.2 (C(Ar)), 127.9(C(Ar)), 144.0 (C(Ar)), 144.9 (C(Ar)), 152.1 (C(Ar)) and 153.7 (C(Ar)).LC/MS (APCI−) t_(r)=2.30 min m/z 327.98 (M−H)⁻; MeOH/H₂O 95/5; HPLCt_(r)=2.60 min (>99.9%). (MeOH)

6-Hydroxy-7-methoxy-2-(2,3-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline56

Yellow powder, 160 mg (49%), mp=101-102° C., R_(f): 0.38 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.69-2.78 (4H, m, 2×CH₂), 3.56 (2H, s, CH₂), 3.72(2H, s, CH₂), 3.78 (3H, s, CH₃O), 3.83 (3H, s, CH₃O), 3.86 (3H, s,CH₃O), 5.41 (1H, br, OH), 6.46 (1H, s, ArH), 6.61 (1H, s, ArH), 6.84(1H, dd, J 7.4 and 2.2 Hz, ArH), 6.99-7.08 (2H, m, ArH), ¹³C NMR (67.5MHz, CDCl₃) δ 28.8 (CH₂), 51.0 (CH₂), 55.7 (CH₂), 55.8 (CH₃O), 56.0(CH₃O), 56.2 (CH₂), 61.0 (CH₃O), 108.9 (CH(Ar)), 111.1 (CH(Ar)), 114.2CH(Ar)), 122.6 (CH(Ar)), 123.9 (CH(Ar)), 126.5 (C(Ar)), 127.1 (C(Ar)),132.3 (C(Ar)), 143.9 (C(Ar)), 144.8 (C(Ar)), 147.8 (C(Ar)) and 152.8(C(Ar)). LC/MS (APCI−) t_(r)=1.93 min m/z 327.98 (M−H)⁻; MeOH/H₂O 80/20;HPLC t_(r)=2.32 min (100%). (MeOH)

6-Hydroxy-7-methoxy-2-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline57

Yellow powder, 170 mg (51%), mp=146-147° C., R_(f): 0.27 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.66-2.79 (4H, m, 2×CH₂), 3.51 (2H, s, CH₂), 3.59(2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.86 (3H, s, CH₃O), 3.87 (3H, s,CH₃O), 5.56 (1H, br, OH), 6.45 (1H, s, ArH), 6.64 (1H, s, ArH), 6.81(1H, d, J 8.2 Hz, ArH), 6.88 (1H, dd, J 8.2 and 1.7 Hz, ArH), 6.96 (1H,d, J 1.7 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.5 (CH₂), 50.7 (CH₂),55.9 (CH₂), 56.0 (2×CH₃O), 56.1 (CH₃O), 62.6 (CH₂), 108.9 (CH(Ar)),110.7 (CH(Ar)), 112.1 CH(Ar)), 114.3 (CH(Ar)), 121.3 (CH(Ar)), 126.2(C(Ar)), 127.1 (C(Ar)), 131.1 (C(Ar)), 144.1 (C(Ar)), 144.9 (C(Ar)),148.2 (C(Ar)) and 149.0 (C(Ar)). LC/MS (APCI−) t_(r)=1.93 min m/z 327.98(M−H)⁻; MeOH/H₂O 80/20; HPLC t_(r)=2.32 min (97.2%). (MeOH)

6-Hydroxy-7-methoxy-2-(2,3,4-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline58

Yellow powder, 265 mg (74%), mp=65-66° C., R_(f): 0.52 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.66-2.759 (4H, m, 2×CH₂), 3.55 (2H, s, CH₂), 3.63(2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.85 (3H, s, CH₃O), 3.88 (6H, s,2×CH₃O), 5.49 (1H, br, OH), 6.46 (1H, s, ArH), 6.63 (1H, s, ArH), 6.65(1H, d, J 8.7 Hz, ArH), 7.09 (1H, d, J 8.7 Hz, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.6 (CH₂), 50.7 (CH₂), 55.6 (CH₂), 56.1 (2×CH₃O), 56.2 (CH₂),60.9 (CH₃O), 61.4 (OCH₃), 107.1 (CH(Ar)), 108.9 (CH(Ar)), 114.2(CH(Ar)), 125.2 (CH(Ar)), 126.1 (C(Ar)), 127.0 (C(Ar)), 142.0 (C(Ar)),142.8 (C(Ar)), 144.0 (C(Ar)), 144.9 (C(Ar)), 152.7 (C(Ar)) and 153.0(C(Ar)). LC/MS (APCI−) t_(r)=1.03 min m/z 358.21 (M−H)⁻; MeOH/H₂O 95/5;HPLC t_(r)=2.50 min (98.8%). (CH₃CN/H₂O)

6-Hydroxy-7-methoxy-2-(2,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline59

Yellow powder, 170 mg (48%), mp=152-153° C., R_(f): 0.48 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.67-2.79 (4H, m, 2×CH₂), 3.57 (2H, s, CH₂), 3.64(2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.81 (3H, s, CH₃O), 3.82 (3H, s,CH₃O), 3.89 (3H, s, CH₃O), 5.61 (1H, br, OH), 6.46 (1H, s, ArH), 6.53(1H, s, ArH), 6.62 (1H, s, ArH), 7.01 (1H, s, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.6 (CH₂), 50.6 (CH₂), 55.3 (CH₂), 55.8 (CH₂), 56.0 (CH₃O),56.2 (CH₃O), 56.6 (CH₃O), 56.8 (OCH₃), 97.6 (CH(Ar)), 108.9 (CH(Ar)),114.2 (CH(Ar)), 114.3 (CH(Ar)), 118.0 (C(Ar)), 126.4 (C(Ar)), 127.1(C(Ar)), 143.1 (C(Ar)), 144.0 (C(Ar)), 144.9 (C(Ar)), 148.5 (C(Ar)) and152.1 (C(Ar)). LC/MS (APCI−) t_(r)=0.60 min m/z 358.21(M−H)⁻; MeOH/H₂O95/5; HPLC t_(r)=2.41 min (98.2%). (CH₃CN/H₂O90/10)

2-(3-Fluorobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline 60

150 mg, 57%, yellow solid, mp 125-127° C. ¹H NMR (270 MHz; DMSO-d₆)2.60-2.63 (4H, m, 2×CH₂), 3.40 (2H, s, CH₂), 3.62 (2H, s, CH₂), 3.67(3H, s, OCH₃), 6.49 (1H, s, CH), 6.54 (1H, s, CH), 7.04-7.21 (3H, m,3×CH), 7.34-7.40 (1H, m, CH), 8.70 (1H, brs, OH). ¹³C NMR (100 MHz;DMSO-d₆) 28.06 (CH₂), 50.62 (CH₂), 55.12 (CH₂), 55.59 (OCH₃), 61.28(CH₂), 110.14 (CH), 113.77 (d, J=21.3 Hz, CH), 115.17 (d, J=19.9 Hz,CH), 115.27 (CH), 124.71 (d, J=2.4 Hz, C), 124.93 (CH), 125.88 (C),130.12 (d, J=8.4 Hz, CH), 141.83 (d, J=6.9 Hz, C), 144.72 (C), 145.87(C), 161.32 (d, J=241.9 Hz, C—F). LC/MS (APCI+) t_(r)=5.03 min, m/z288.35 (M⁺+H). HRMS (ES+) calcd. for C₁₇H₁₉FNO₂ (M⁺+H) 288.1394, found288.1393. HPLC t_(r)=3.68 min (>98%).

2-(3-Isopropoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline61

134 mg, 70%, pale yellow solid. mp 143-146° C. ¹H NMR (270 MHz; CDCl₃)1.31 (6H, d, J=5.9 Hz, 2×CH₃), 2.68-2.77 (4H, m, 2×CH₂), 3.52 (2H, s,CH₂), 3.62 (2H, s, CH₂), 3.81 (3H, s, OCH₃), 4.55 (1H, Septet, J=5.9 Hz,CH), 6.45 (1H, s, CH), 6.63 (1H, s, CH), 6.76-6.80 (1H, m, CH),6.92-6.94 (2H, m, 2×CH), 7.21 (1H, t, J=7.7 Hz, CH). ¹³C NMR (67.5 MHz;CDCl₃) 22.18 (CH₃), 28.59 (CH₃), 50.89 (CH₂), 55.87 (CH₃), 56.05 (OCH₃),62.82 (CH₂), 69.76 (CH), 108.90 (CH), 114.31 (CH), 114.63 (CH), 116.47(CH), 121.34 (CH), 126.24 (C), 127.10 (C), 129.30 (CH), 140.16 (C),144.03 (C), 144.91 (C), 158.03 (C). LC/MS (APCI−) t_(r)=1.1 min, m/z326.09 (M−H)⁻. HPLC t_(r)=2.60 min (>99%). Anal. Calcd. for C₂₀H₂₅NO₃:C, 73.37; H, 7.70; N, 4.28. Found C, 73.5; H, 7.90; N, 4.13%.

A solution of2-benzyl-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline(1 mmol) in THF (20 mL) was stirred with a 1M solution of TBAF/THF (1.1mmol) for 60 minutes at RT. After addition of water, the organics wereextracted with ethyl acetate (80 mL) and the organic layer washed withwater, brine, dried (MgSO₄), filtered and concentrated under reducedpressure. The residual oil/solid was purified by flash chromatography(hexane/ethyl acetate).

6-Hydroxy-7-methoxy-2-(3-acetylbenzyl)-1,2,3,4-tetrahydroisoquinoline 62

Yellow solid, 220 mg (71%), mp=132-134° C., R_(f): 0.22 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CDCl₃) δ 2.60 (s, 3H, CH₃CO), 2.67-2.80 (4H, m,2×CH₂), 3.52 (2H, s, CH₂), 3.71 (2H, s, CH₂), 3.79 (3H, s, OCH₃), 5.55(1H, br, OH), 6.44 (1H, s, ArH), 6.64 (1H, s, ArH), 7.42 (1H, t, J 7.7Hz, ArH), 7.62 (1H, dt, J 7.7 and 1.6 Hz, ArH), 7.85 (1H, dt, J 7.7 &1.2 Hz, ArH), 7.95 (1H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 26.9(CH₃CO), 28.6 (CH₂), 51.0 (CH₂), 55.8 (CH₂), 56.0 (CH₃O), 62.5 (CH₂),108.8 (CH(Ar)), 114.3 (CH(Ar)), 126.0 (C(Ar)), 127.0 (C(Ar)), 127.3(CH(Ar)), 128.7 (CH(Ar)), 129.0 (CH(Ar)), 134.0 (CH(Ar)), 137.3 (C(Ar)),139.3 (C(Ar)), 144.1 (C(Ar)), 144.9 (C(Ar)) and 198.5 (CO). LC/MS(APCI+) t_(r)=4.06 min m/z 312.47 (M⁺+H); MeOH/H2O 95/5 to 50/50 in 5min. HPLC t_(r)=4.68 min (92%). (CH₃CN/H₂O 90/10)

2-(3-Ethoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline 63

Yellow powder, 155 mg (50%), mp=105-106° C., R_(f): 0.31 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 1.39 (3H, t, J 7.2 Hz, CH₃), 2.66-2.80(4H, m, 2×CH₂), 3.53 (2H, s, CH₂), 3.64 (2H, s, CH₂), 3.79 (3H, s,CH₃O), 4.02 (2H, q, J 7.2 Hz, CH₂), 6.45(1H, s, ArH), 6.63 (1H, s, ArH),6.80 (1H, ddd, J 8.0, 2.2 and 1.0 Hz, ArH), 6.93-6.96 (2H, m, ArH), 7.22(1H, t, J 8.0 Hz, 1H, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 15.0 (CH₃), 28.5(CH₂), 50.8 (CH₂), 55.8 (CH₂), 56.0 (CH₃O), 62.8 (CH₂), 63.4 (CH₂O),108.9 (CH(Ar)), 113.3 (CH(Ar)), 114.3 (CH(Ar)), 115.1 (CH(Ar)), 121.4(CH(Ar)), 126.1 (C(Ar)), 127.0 (C(Ar)), 129.3 (CH(Ar)), 140.0 (C(Ar)),144.0 (C(Ar)), 144.9 (C(Ar)) and 159.1 (C(Ar)). LC/MS (APCI+) t_(r)=4.82min m/z 314.55 (M⁺+H); MeOH/H₂O 50/50 to 95/5 (5 min); HPLC t_(r)=5.68min (94.6%). (CH₃CN/H₂O 90/10).

2-(3-Cyanobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline 64

157 mg, 73%, pale yellow oil. Crystallisation from diethyl ether andhexane afford a pure sample. mp 113-155° C. ¹H NMR (400 MHz; CDCl₃) 2.71(2H, t, J 5.6 Hz, CH₂), 2.79 (2H, t, J 6.0 Hz, CH₂), 3.51 (2H, s, CH₂),3.68 (2H, s, CH₂), 3.80 (3H, s, OCH₃), 6.45 (1H, s, CH), 6.65 (1H, s,CH), 7.43 (1H, t, J 8.0 Hz, CH), 7.64 (1H, d, J 8.0 Hz, CH) & 7.69 (1H,s, CH). ¹³C NMR (100 MHz; CDCl₃) 28.33 (CH₂), 50.89 (CH₂), 55.60 (CH₃),55.93 (CH₂), 61.75 (CH₂), 108.69 (CH), 112.34 (C), 114.23 (CH), 118.91(C), 125.48 (C), 126.65 (C), 129.12 (CH), 130.88 (CH), 132.37 (CH),133.38 (CH), 140.17 (C), 144.09 (C) & 144.91 (C). LC/MS (APCI−)t_(r)=3.96 min, m/z 293.45 (M⁺−H). HPLC t_(r)=2.94 min (>95%)

2-(4-Cyanobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline 65

160 mg, 76%, yellow powder. mp 165-166.5° C. ¹H NMR 270 MHz; CDCl₃)2.68-2.72 (2H, m, CH₂), 2.76-2.80 (2H, m, CH₂), 3.51 (2H, s, CH₂), 3.70(2H, s, CH₂), 3.80 (3H, s, OCH₃), 5.54 (1H, brs, OH), 6.44 (1H, s, CH),6.65 (1H, s, CH), 7.51 (2H, ˜d, J 8.7 Hz, 2×CH), 7.61 (2H, ˜d, J 8.4 Hz,2×CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.52 (CH₂), 51.11 (CH₂), 55.86 (OCH₃),56.06 (CH₂), 62.28 (CH₂), 108.76 (CH), 110.97 (C), 114.34 (CH), 119.11(C), 126.68 (C), 126.79 (C), 129.56 (2×CH), 132.28 (2×CH), 144.18 (C),144.52 (C), 144.99 (C). LC/MS (APCI+) t_(r)=3.95 min, m/z 295.93 (M⁺+H).HRMS (ES+) calcd. for C₁₈H₁₉N₂O₂ (M⁺+H) 295.1441, found 295.1539. HPLCt_(r)=3.40 min (>95%).

6-Hydroxy-7-methoxy-2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline 66

213 mg, 78%, yellow solid. mp 127-128° C. ¹H NMR (270 MHz; CDCl₃)2.71-2.79 (4H, m, 2×CH₂), 3.54 (2H, s, CH₂), 3.74 (2H, s, CH₂), 3.80(3H, s, OCH₃), 5.51 (1H, s, OH), 6.44 (1H, s, CH), 6.65 (1H, s, CH),7.49 (1H, t, J 7.9 Hz, CH), 7.75 (1H, d, J 7.9 Hz, CH), 8.12 (1H, ddd, J8.2, 2.5, 1.0 Hz, CH), 8.24 (1H, t, J 1.7 Hz, CH). ¹³C NMR (67.5 MHz;CDCl₃) 28.49 (CH₂), 51.03 (CH₂), 55.76 (CH₂), 56.06 (OCH₃), 61.89 (CH₂),108.79 (CH), 114.35 (CH), 122.39 (CH), 123.84 (CH), 125.639 (C), 126.79(C), 126.36 (CH), 135.20 (CH), 140.99 (C), 144.19 (C), 145.02 (C),148.43 (C). LC/MS (APCI+) t_(r)=4.32 min, m/z 315.49 (M⁺+H). HRMS (ES+)calcd. for C₁₇H₁₉N₂O₄ (M⁺+H) 315.139, found 315.1338. HPLC t_(r)=3.04min (>95%).

2-(3-Chlorobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline 67

195 mg, 92%, yellow solid. mp 118-119.5° C. ¹H NMR (270 MHz; CDCl₃)2.68-2.72 (2H, m, CH₂), 2.76-2.80 (2H, m, CH₂), 3.51 (2H, s, CH₂), 3.62(2H, s, CH₂), 3.80 (3H, s, OCH₃), 6.45 (1H, s, CH), 6.65 (1H, s, CH),7.22-7.27 (3H, m, 3×CH), 7.40 (1H, d, J 1.2 Hz, CH). ¹³C NMR (67.5 MHz;CDCl₃) 28.53 (CH₂), 51.0 (CH₂), 55.78 (OCH₃), 56.06 (CH₂), 62.26 (CH₂),108.85 (CH), 114.34 (CH), 125.89 (C), 126.91 (C), 127.25 (CH), 127.38(CH), 129.13 (CH), 129.65 (CH), 134.29 (C), 140.76 (C), 144.13 (C),144.97 (C). LC/MS (APCI+) t_(r)=4.92 min, m/z 304.53 (M⁺+H). HPLCt_(r)=4.18 min (>99%). Anal. Calc. for C₁₇H₁₈ClNO₂: C, 67.21; H, 5.97;N, 4.61. Found: C, 67.1; H, 6.05; N, 4.46%.

6-Hydroxy-7-methoxy-2-(3-trifluoromethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline68

95 mg, 60%, yellow solid. mp 122-124° C. ¹H NMR (270 MHz; CDCl₃)2.67-2.72 (2H, m, CH₂), 2.76-2.81 (2H, m, CH₂), 3.53 (2H, s, CH₂), 3.67(2H, s, CH₂), 3.81 (3H, s, OCH₃), 5.47 (1H, s, OH), 6.45 (1H, s, CH),6.65 (1H, s, CH), 7.09-7.12 (1H, m, CH), 7.26-7.37 (3H, m, 3×CH). ¹³CNMR (67.5 MHz; CDCl₃) 28.50 (CH₂), 50.89 (CH₂), 55.79 (CH₂), 56.05(OCH₃), 62.07 (CH₂), 108.87 (CH), 114.37 (CH), 119.56 (CH), 121.43 (CH),125.93 (C), 126.97 (C), 127.30 (CH), 129.64 (CH), 141.19 (C), 144.16(C), 145.0 (C), 149.47 (C). LC/MS (ES+) t_(r)=1.41 min, m/z 354.57(M⁺+H). HPLC t_(r)=4.9 min (>97%).

2-(2-Hydroxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline69

78 mg, 71%, colourless solid. mp 151.9-152.6° C. ¹H NMR (270 MHz; CDCl₃)2.83 (4H, brs, 2×CH₂), 3.65 (2H, s, CH₂), 3.80 (3H, s, OCH₃), 3.86 (2H,s, CH₂), 6.46 (1H, s, CH), 6.66 (1H, s, CH), 6.77-6.84 (2H, m, 2 ×CH),7.02 (1H, brd, J 7.4 Hz, CH), 7.19 (1H, td, J 7.7, 1.6 Hz, CH). ¹³C NMR(67.5 MHz; CDCl₃) 28.07 (CH₂), 50.26 (CH₂), 55.04 (CH₂), 56.04 (OCH₃),61.16 (CH₂), 108.76 (CH), 114.21 (CH), 116.30 (CH), 119.17 (CH), 121.39(C), 124.63 (C), 126.28 (C), 128.72 (CH), 128.93 (CH), 144.39 (C),145.14 (C), 158.08 (C). LC/MS (APCI−) t_(r)=1.27 min, m/z 283.95 (M−H)⁻.HPLC t_(r)=1.63 min (>98%).

2-(3-Hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol 70

A solution of6-benzyloxy-2-(3-(hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline(340 mg, 0.91 mmol) in THF (20 mL) and methanol (10 mL) was stirred with10% Pd/C (40 mg) under hydrogen for 0.5 h. After filtration throughcelite and evaporation of the solvents under reduced pressure, theresidual oil was purified by flash chromatography (ethyl acetate) giving200 mg (78%)of a yellow powder, mp=177-178° C.; Re. 0.29 (EtOAc), ¹H NMR(270 MHz, CDCl₃/CD₃COCD₃ 5:1) δ 2.41-2.51 (4H, m, 2×CH₂), 3.24 (2H, s,CH₂), 3.34 (2H, s, CH₂), 3.53 (3H, s, CH₃O), 6.21 (1H, s, ArH), 6.35(1H, s, ArH), 6.49 (1H, ddd, J 7.2, 3.0 & 1.2 Hz, ArH), 6.61 (1H, d, J7.2 Hz, ArH), 6.64 (1H, d, J 3.0 Hz, ArH), 6.88 (1H, t J 7.2 Hz, 1H,ArH). ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCD₃ 5:1) δ 28.3 (CH₂), 50.7 (CH₂),55.4 (CH₂), 55.7 (CH₃O), 62.3 (CH₂), 109.0 (CH(Ar)), 114.0 (CH(Ar)),114.3 (CH(Ar)), 115.8 (CH(Ar)), 120.2 (CH(Ar)), 125.6 (C(Ar)), 126.5(C(Ar)), 129.1 (CH(Ar)), 144.1 (C(Ar)), 144.3 (C(Ar)), 145.1 (C(Ar)) and156.9 (C(Ar)). LC/MS (APCI+) t_(r)=1.48 min m/z 286.52 (M⁺+H); MeOH/H₂O50/50 to 95/5 (5 min); HPLC t_(r)=4.43 min (99.16%). (CH₃CN/H₂O 90/10)

2-(3-(Methoxycarbonyl)benzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline70A

From 36A. Purification (flashmaster: 20 g, gradient elution hex/EtOAc)afforded the title compound (159 mg, 77%) as a yellow solid. mp 156-158°C. ¹H NMR (270 MHz; CDCl₃) 2.68-2.78 (4H, m, 4×CH), 3.51 (2H, s, 2×CH),3.69 (2H, s, 2×CH), 3.79 (3H, s, OCH₃), 3.90 (3H, s, OCH₃) 5.51 (1H,brs, OH), 6.44 (1H, s, CH), 6.64 (1H, s, CH), 7.40 (1H, t, J=7.7 Hz,CH), 7.61 (1H, d, J=7.6 Hz, CH), 7.92 (1H, dt, J 7.7, 1.3 Hz, CH), 8.03(1H, brs, CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.54 (CH₂), 50.97 (CH₂), 52.22(CH₃), 55.79 (CH₂), 56.05 (CH₃), 62.46 (CH₂), 108.86 (CH), 114.32 (CH),125.95 (C), 126.95 (C), 128.54 (CH), 130.27 (CH), 133.83 (CH), 139.01(C), 144.11 (C), 144.96 (C), 167.31 (C). LC/MS (APCI−) t_(r)=0.92 min,m/z 326.15 (M−H)⁻. HPLC t_(r)=1.55 min (>99%). Anal. Calcd. forC₁₉H₂₁NO₄: C, 69.71; H, 6.47; N, 4.28. Found: C, 4.22; H, 69.6; N,6.41%.

6,7-Dimethoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline70B

A mixture of 6,7-dimethoxytetrahydroisoquinoline hydrochloride (0.23 g,1 mmol), 3,4,5-trimethoxybenzyl chloride (0.26 g, 1.2 mmol) in TEA (0.5mL) and ethanol (2.5 mL) was subjected to microwave heating to 130° C.for 1 h. The mixture was poured into water, the organics extracted withethyl acetate and the organic layer washed with water, brine, dried(MgSO₄), filtered and concentrated under reduced pressure. The resultantcrude solid was purified by flash chromatography (hexane/ethyl acetate6:1 to 1:1) to give a white solid which was stirred in diethyl ether,filtered and dried under vacuum to afford a white powder (230 mg, 62%),mp=118-119° C., R_(f): 0.43 (EtOAc), ¹H NMR (270 MHz, CDCl₃) δ 2.70 (2H,t, J=5.6 Hz, CH₂), 2.81 (2H, t, J=5.6 Hz, CH₂), 3.55 (2H, s, CH₂), 3.59(2H, s, CH₂), 3.81 (3H, s, CH₃O), 3.83 (3H, s, CH₃O), 3.84 (3H, s,CH₃O), 3.85 (6H, s, CH₃O), 6.50 (1H, s, ArH), 6.60 (1H, s, ArH), 6.62(2H, s, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ 28.8 (CH₂), 50.7 (CH₂), 55.9(CH₂), 56.0 (2×CH₃O), 56.2 (2×CH₃O), 61.0 (CH₃O), 63.1 (CH₂), 105.6(2×CH(Ar)), 109.5 (CH(Ar)), 111.4 (CH(Ar)), 126.3 (C(Ar)), 126.8(C(Ar)), 134.5 (C(Ar)), 136.7 (C(Ar)), 147.3 (C(Ar)), 147.6 (C(Ar)),153.2 (2×CH(Ar)). LC/MS (ES+) t_(r)=0.93 min m/z 374.27 (M+H)⁺; MeOH/H₂O95/5; HPLC t_(r)=3.62 min (99.2%). (CH₃CN/H₂O 70:30)

7-Methoxy-6-O-acetyl-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline70C

A solution of 6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline 54 (108 mg, 0.3 mmol),triethylamine (0.21 mL, 1.6 mmol) and acetic anhydride (0.16 mL, 1.6mmol) in CHCl₃ (10 mL) was stirred at rt for 24 hours. After additionCHCl₃ (30 mL), the organic layer was washed with water (4×30 mL), brine,dried (MgSO₄), filtered and the solvent evaporated under reducedpressure. The resultant yellow solid was stirred in diethyl ether,filtered, dried under vacuum to yield a white powder (95 mg, 79%),mp=143-144° C., R_(f): 0.47 (EtOAc), ¹H NMR (270 MHz, CDCl₃) δ 2.28 (3H,s, CH₃), 2.69-2.83 (4H, m, 2×CH₂), 3.60 (4H, s, 2×CH₂), 3.75 (3H, s,CH₃O), 3.84 (3H, s, CH₃O), 3.85 (6H, s, CH₃O), 6.58 (1H, s, ArH), 6.62(2H, s, ArH), 6.77 (1H, s, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ 20.7(CH₃),28.3 (CH₂), 50.5 (CH₂), 55.9 (CH₂), 56.0 (CH₃O), 56.2 (2×CH₃O), 60.9(CH₃O), 62.8 (CH₂), 105.7 (2×CH(Ar)), 110.5 (CH(Ar)), 122.7 (CH(Ar)),124.1 (C(Ar)), 126.5 (C(Ar)), 133.3 (C(Ar)), 136.9 (C(Ar)), 138.1(C(Ar)), 149.1 (C(Ar)), 153.3 (2×CH(Ar)) and 169.4 (CO). LC/MS (ES+)t_(r)=0.96 min m/z 402.24(M+117 ; MeOH/H₂O 95/5; HPLC t_(r)=1.99 min(99%). (CH₃CN/H₂O 90:10).

7-Methoxy-6-O-methanesulfonyl-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline70D

A solution of6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline54 (80 mg, 0.22 mmol) in pyridine (1 mL) was cooled to 0° C. andmethanesulfonyl chloride (20 μL, 0.26 mmol) added. The solution wasstirred for 2 hours at 0° C. then 4 hours at rt. After addition of water(5 mL), the organic were extracted with ethyl acetate, the organic layerwas washed with water, brine, dried (MgSO₄), filtered and concentratedunder reduced pressure. The resultant solid was purified by flashchromatography (hexane/ethyl acetate 1:1) to give 80 mg of white solidwhich was stirred in diethyl ether, filtered and dried. White powder (70mg, 73%), m.p. 134-135° C., R_(f)=0.58 (ethyl acetate), ¹H NMR (270 MHz,CDCl₃) δ 2.68-2.84 (4H, m, 2×CH₂), 3.15 (3H, m, CH₃), 3.57 (2H, s, CH₂),3.59 (2H,s, CH₂), 3.81 (3H, s, CH₃O), 3.83 (3H, s, CH₃O), 3.85 (6H, s,CH₃O), 6.61 (2H, s, ArH), 7.04 (1H, s, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ28.3 (CH₂), 38.2 (CH₃), 50.4 (CH₂), 55.9 (CH₂), 56.1 (CH₃O), 56.2(2×CH₃O), 61.0 (CH₃O), 62.9 (CH₂), 70.8 (CH₂), 105.6 (2×CH(Ar)), 110.9(CH(Ar)), 124.5 (CH(Ar)), 127.4 (C(Ar)), 134.2 (C(Ar)), 135.0 (C(Ar)),136.7 (C(Ar)), 137 (C(Ar)), 149.3 (2×C(Ar)), 153.3 (C(Ar)). LC/MS (ES+)t_(r)=0.66 min m/z 438.14 (M+1)⁺; MeOH/H₂O 95/5. HPLC t_(r)=1.87 min(97.4%). (acetonitrile/water90/10).

Synthesis of 6-O-sulfamoyl-2-benzyl-1,2,3,4-tetrahydroisoquinolines

A solution of 6-hydroxy-2-benzyl-1,2,3,4-tetrahydroisoquinoline (0.5mmol) and sulfamoyl chloride (1 mmol) in DMA (1 mL) was stirred at rtunder nitrogen for 24 hours. After addition of water (5 mL) and KHCO₃(150 mg, 1.5 mmol) the reaction mixture was extracted into ethyl acetate(2×50 mL), the organic layers washed with water and brine, then dried(MgSO₄) and evaporated. The crude product was purified by flashchromatography (hexane/ethyl acetate or DMC/ethyl acetate)

2-(3-Methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline 71

White solid, 140 mg (69%), mp 139-140° C., R_(f): 0.25 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.72 (2H, t, J 5.4 Hz, CH₂), 2.88 (2H,t, J 5.4 Hz, CH₂), 3.59 (2H, s, CH₂), 3.65 (2H, s, CH₂), 3.79 (3H, s,CH₃O), 4.30 (2H, br, NH₂), 6.82 (1H, ddd, J 8.2, 2.5 and 1.0 Hz, ArH),6.92-6.96 (2H, m, ArH), 6.99-7.03 (3H, m, ArH), 7.23 (1H, t, J 8.2 Hz,ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 29.1 (CH₂), 50.1 (CH₂), 55.3 (CH₃O),55.5 (CH₂), 62.6 (CH₂), 112.9 (CH(Ar)), 114.7 (CH(Ar)), 119.4 (CH(Ar)),121.6 (CH(Ar)), 122.0 (CH(Ar)), 128.1 (CH(Ar)), 129.4 (CH(Ar)), 134.1(C(Ar)), 136.5 (C(Ar)), 139.5 (C(Ar)), 148.3 (C(Ar)) and 159.8 (C(Ar)).LC/MS (APCI+) t_(r)=4.23 min m/z 349.56 (M⁺+H); MeOH/H₂O 50/50 to 95/5in 5 min; HPLC t_(r)=3.95 min (96.3%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(3-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline72

Light yellow powder, 150 mg (80%), mp 144-145° C., R_(f): 0.21 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃/CD₃OD 5/1) δ 2.66-2.77 (4H,m, 2×CH₂), 3.10 (2H, br, NH₂), 3.51 (2H, s, CH₂), 3.60 (2H, s, CH₂),3.74 (3H, s, CH₃O), 3.75 (3H, s, CH₃O), 6.55 (1H, s, ArH), 6.79 (1H, d,J 7.9 Hz, ArH), 6.82 (2H, s, ArH), 7.04 (1H, s, ArH), 7.21 (1H, t, J 7.9Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃OD 5/1) 8 27.8 (CH₂), 50.4 (CH₂),55.3, (CH₃O), 55.6 (CH₂), 56.2 (CH₃O), 62.7 (CH₂), 110.9 (CH(Ar)) 112.9(CH(Ar)), 114.8 (CH(Ar)), 121.7 (CH(Ar)), 123.8 (CH(Ar)), 126.9 (C(Ar)),129.4 (C(Ar)), 133.9 (C(Ar)), 137.7 (C(Ar)) 138.9 (C(Ar)), 149.6 (C(Ar))and 159.7 (C(Ar)). LC/MS (APCI+) t_(r)=4.21 min m/z 379.34 (M⁺+H); HPLCt_(r)=3.01 min (99.6%). (CH₃CN/H₂O 70/30)

7-Methoxy-2-(4-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline73

Light yellow powder, 140 mg (75%), mp 104-105° C., R_(f): 0.42 (ethylacetate), ¹H NMR (270 MHz, CDCl₃) δ 2.69-2.82 (4H, m, 2×CH₂), 3.54 (2H,s, CH₂), 3.61 (2H, s, CH₂), 3.78 (3H, s, CH₃O), 3.79 (3H, s, CH₃O), 6.59(1H, s, ArH), 6.88 (2H, m, ArH), 7.07 (1H, s, ArH), 7.26 (2H, m, ArH),¹³C NMR (67.5 MHz, CDCl₃) δ 28.2 (CH₂), 50.4 (CH₂), 55.4, (CH₃O), 55.6(CH₂), 56.3 (CH₃O), 62.1 (CH₂), 111.1 (CH(Ar)), 113.7 (2×CH(Ar)), 124.2(CH(Ar)), 127.7 (C(Ar)), 129.9 (C(Ar)), 130.4 (2×CH(Ar)), 134.4 (C(Ar)),138.2 (C(Ar)), 150.4 (C(Ar)) and 159.6 (C(Ar)). LC/MS (APCI+) t_(r)=4.12min m/z 379.34 (M⁺+H); HPLC t_(r)=2.15 min (98.9%). (CH₃CN/H₂O 90/10);HRMS (Electrospray) calcd. for C₁₈H₂₂N₂O₅S (MH⁺), 379.1322 found.379.1322

2-Benzyl-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline 74

Light yellow powder, 55 mg (79%), mp 113-114° C., R_(f): 0.61 (ethylacetate), ¹H NMR (270 MHz, CDCl₃) δ 2.71-2.84 (4H, m, 2×CH₂), 3.56 (2H,s, CH₂), 3.68 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 4.97 (1H, br, OH), 6.60(1H, s, ArH), 7.07 (1H, s, ArH), 7.26-7.40 (5H, m, ArH), ¹³C NMR (67.5MHz, CDCl₃) δ 28.2 (CH₂), 50.5 (CH₂), 55.7 (CH₂), 56.4 (CH₃O), 62.6(CH₂), 111.2 (CH(Ar)), 124.2 (CH(Ar)), 127.4 (CH(Ar)), 127.7 (C(Ar)),128.5 (2×CH(Ar)) and 129.2 (2×CH(Ar)), 134.9 (C(Ar)), 137.3 (C(Ar)),138.0 (C(Ar)) and 149.3 (C(Ar)). LC/MS (APCI+) t_(r)=4.18 min m/z 349.37(M⁺+H); HPLC t_(r)=2.11 min (97.7%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(2-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline75

Light yellow powder, 105 mg (55%), mp 126-127° C., R_(f): 0.43 (ethylacetate), ¹H NMR (270 MHz, CDCl₃/CD₃OD 5/1) 82.78 (4H, m, 2×CH₂), 3.48(2H, br, NH₂), 3.62 (2H, s, CH₂), 3.73 (2H, s, CH₂), 3.79 (3H, s, CH₃O),3.83 (3H, s, CH₃O), 6.61 (1H, s, ArH), 6.90 (1H, d, J 7.9 Hz, ArH), 6.95(1H, dt, J 7.4 and 1.0 Hz, ArH), 7.09 (1H, s, ArH), 7.25-7.36 (2H, m,ArH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃OD 5/1) δ 27.6 (CH₂), 50.3 (CH₂), 55.6(2×CH₃O), 55.6 (CH₂), 60.7 (CH₂), 110.6 (CH(Ar)) 111.0 (CH(Ar)), 120.5(CH(Ar)), 123.8 (CH(Ar)), 124.8 (C(Ar)), 126.8 (C(Ar)), 128.9 (CH(Ar)),131.2 (CH(Ar)), 133.8 (C(Ar)), 137.5 (C(Ar)), 149.7 (C(Ar)) and 158.1(C(Ar)). LC/MS (APCI+) t_(r)=3.96 min m/z 379.34 (M⁺+H); HPLC t_(r)=2.45min (99.6%). (CH₃CN/H₂O 90/10).

2-(3,5-Dimethoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline76

Light yellow powder, 145 mg (71%), mp 147-148° C., R_(f): 0.55 (ethylacetate), ¹H NMR (270 MHz, CDCl₃/CD₃OD 5/1) δ 2.63-2.77 (4H, m, 2×CH₂),3.48 (2H, s, CH₂), 3.54 (2H, s, CH₂), 3.61 (2H, br, NH₂), 3.71 (6H, s,2×CH₃O), 3.72 (3H, s, CH₃O), 6.30 (1H, t, J 2.2 Hz, ArH), 6.46 (1H, d, J2.2 Hz, ArH), 6.53 (1H, s, ArH),7.02 (1H, s, ArH), ¹³C NMR (67.5 MHz,CDCl₃/CD₃OD 5/1) δ 27.7 (CH₂), 50.4 (CH₂), 55.3 (2×CH₃O), 55.6 (CH₂),56.0 (CH₃O), 62.7 (CH₂), 99.3 (CH(Ar)), 106.1 (CH(Ar))), 110.8 (CH(Ar)),123.6 (CH(Ar)), 126.6 (C(Ar)), 133.8 (C(Ar)), 137.4 (C(Ar)), 139.6(C(Ar)), 149.6 (C(Ar)) and 160.7 (C(Ar)). LC/MS (APCI+) t_(r)=4.20 minm/z 409.25 (M⁺+H); HPLC t_(r)=2.05 min (99.6%). (CH₃CN/H₂O 90/10).

7-Methoxy-2-(3-methylbenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline77

Yellow powder, 120 mg (67%), mp=142-143° C., R_(f): 0.41 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.34 (3H, s, CH₃), 2.71-2.84 (4H, m,2×CH₂), 3.56 (2H, s, CH₂), 3.64 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 5.02(2H, br, NH₂), 6.60 (1H, s, ArH), 7.07 (1H, s, ArH), 7.10-7.22 (4H, m,ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 21.5 (CH₃), 28.2 (CH₂), 50.5 (CH₂),55.7 (CH₂), 56.4 (CH₃O), 62.7 (CH₂), 111.2 (CH(Ar)), 124.2 (CH(Ar)),126.3 (CH(Ar)), 127.6 (C(Ar)), 128.1 (CH(Ar)), 128.3 (CH(Ar)), 130.0(CH(Ar)), 134.8 (C(Ar)), 137.3 (C(Ar)), 137.8 (C(Ar)), 138.2 (C(Ar)),149.3 (C(Ar)). LC/MS (APCI−) t_(r)=4.59 min m/z 361.40 (M HPLCt_(r)=3.90 min (96.3%). (MeOH/H₂O 70/30).

7-Methoxy-2-(3-phenoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline78

Yellow powder, 180 mg (82%), mp=68-69° C., R_(f): 0.36 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68-2.79 (4H, m, 2×CH₂), 3.56 (2H, s,CH₂), 3.64 (2H, s, CH₂), 3.80 (3H, s, CH₃O), 4.80 (2H, br, NH₂), 6.59(1H, s, ArH), 6.90 (1H, dd, J 7.9, 1.7 Hz, ArH), 6.98-7.02 (2H, m, ArH),7.05-7.12 (4H, m, ArH), 7.25-7.35 (3H, m, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.2 (CH₂), 50.4 (CH₂), 55.7 (CH₂), 56.4 (CH₃O), 62.3 (CH₂),111.2 (CH(Ar)), 117.8 (CH(Ar)), 118.9 (2×CH(Ar)), 119.6 (CH(Ar)), 123.3(CH(Ar)), 124.0 (CH(Ar)), 124.1 (CH(Ar)), 127.6 (C(Ar)), 129.7 (CH(Ar)),129.9 (2×CH(Ar)), 134.7 (C(Ar)), 137.3 (C(Ar)), 140.2 (C(Ar)), 149.3(C(Ar)), 157.2 (C(Ar)) and 157.4 (C(Ar)). LC/MS (APCI−) t_(r)=5.05 minm/z 439.66 (M⁺−H); HPLC t_(r)=2.20 min (99.7%). (MeOH/H₂O 90/10).

7-Methoxy-2-(3-(O-sulfamoyl)benzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline79

Light yellow powder, 170 mg (76%), R_(f): 0.68 (EtOAc), ¹H NMR (270 MHz,CDCl₃/CD₃COCD₃ 5:1) δ 2.44-2.55 (4H, m, 2×CH₂), 3.31 (2H, s, CH₂), 3.43(2H, s, CH₂), 3.55 (3H, s, CH₃O), 6.05 (2H, br, NH₂), 6.30 (2H, br,NH₂), 6.36 (1H, s, ArH), 6.80 (1H, s, ArH), 6.96 (1H, dt, J 7.7, 1.0 Hz,ArH), 7.03-7.11 (3H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCD₃ 5:1) δ28.1 (CH₂), 50.4 (CH₂), 55.5 (CH₂), 55.8(CH₃O), 61.7 (CH₂), 110.7(CH(Ar)), 120.8 (CH(Ar)), 122.4 (CH(Ar)), 123.7 (CH(Ar)), 126.6 (C(Ar)),127.0 (CH(Ar)), 129.3 (CH(Ar)), 134.0 (C(Ar)), 137.3 (C(Ar)), 140.5(C(Ar)), 149.7 (C(Ar)) and 150.4 (C(Ar)). LC/MS (APCI+) t_(r)=3.26 minm/z 444.32 (M⁺+H); MeOH/H2O 50/50 to 95/5 (5 min); HPLC t_(r)=3.20 min(100%). (CH3CN/H2O 90/10).

2-(3-Ethoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline80

Light yellow powder, 140 mg (71%), mp=64-65° C., R_(f): 0.18(Hexane/EtOAc 1:1), ¹H NMR (270 MHz, CDCl₃) δ 1.39 (3H, t, J 6.9, CH₃),2.69-2.84 (4H, m, 2×CH₂), 3.56 (2H, s, CH₂), 3.64 (2H, s, CH₂), 3.80(3H, s, CH₃O), 4.02 (2H, q, J 6.9, CH₂), 5.00 (2H, br, NH₂), 6.59(1H, s,ArH), 6.80 (1H, dd, J 7.9, 2.0, ArH), 6.91-6.94 (2H, m, ArH), 7.06 (1H,s, ArH), 7.22 (1H, t, J 7.9, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 15.0(CH₃), 28.2 (CH₂), 50.5 (CH₂), 55.7 (CH₂), 56.4 (CH₃O), 62.6 (CH₂), 63.5(CH₂O), 111.2 (CH(Ar)), 113.4 (CH(Ar)), 115.1 (CH(Ar)), 121.4 (CH(Ar)),124.1 (CH(Ar)), 127.7 (C(Ar)), 129.4 (CH(Ar)), 134.8 (C(Ar)), 137.30(C(Ar)), 139.60 (C(Ar)), 149.3 (C(Ar)) and 159.2 (C(Ar)). LC/MS (APCI+)t_(r)=4.53 min m/z 393.43 (M⁺+H); MeOH/H₂O 50/50 to 95/5 (5 min); HPLCt_(r)=4.35 min (95.2%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(pyridin-3-ylmethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline81

Yellow powder, 110 mg (63%); mp=139-140° C., R_(f): 0.24 (EtOAc/MeOH10:1), ¹H NMR (270 MHz, CDCl₃/CD₃COCDl₃ 5:1) δ 2.47-2.58 (4H, m, 2×CH₂),3.33 (2H, s, CH₂), 3.40 (2H, br, NH₂), 3.46 (2H, s, CH₂), 3.54 (3H, s,CH₃O), 6.37 (1H, s, ArH), 6.83 (1H, s, ArH), 7.09 (1H, dd, J 7.7, 4.9Hz, PyrH), 7.55 (1H, d, J 7.7 Hz, 1H, PyrH), 8.22 (1H, d, J 4.9 Hz, 1H,PyrH), 8.29 (s, 1H, PyrH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCDl₃ 5:1) δ27.8 (CH₂), 50.3 (CH₂), 55.4 (CH₂), 55.7 (CH₃O), 59.4 (CH₂), 63.5(CH₂O), 110.6 (CH(Ar)), 122.3 (C(Ar)), 123.6 (CHpyr), 123.7 (CH(Ar)),126.3 (C(Ar)), 133.4 (C(Ar)), 133.7 (Cpyr), 137.2 (CHpyr), 137.5(C(Ar)), 148.1 (CHpyr) and 149.7 (CHpyr). LC/MS (APCI+) t_(r)=2.97 minm/z 350.52 (M⁺+H); MeOH/H₂O 50/50 to 95/5 (5 min); HPLC t_(r)=3.38 min(96.2%). (CH₃CN/H₂O 90/10)

2-(3-Acetylbenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline82

Yellow powder, 130 mg (66%), mp=144-145° C., R_(f): 0.36 (EtOAc), ¹H NMR(270 MHz, CDCl₃/CD₃COCD₃ 4:1) δ 2.15 (s, 3H, CH₃), 2.27-2.38 (4H, m,2×CH₂), 3.12 (2H, s, CH₂), 3.29 (2H, s, CH₂), 3.33 (3H, s, OCH₃), 6.19(3H, br, NH₂ and ArH), 6.60 (1H, s, ArH), 7.00 (1H, t, J 7.7 Hz, ArH),7.17 (1H, dt, J 7.7 and 1 Hz, ArH), 7.44 (1H, dt, J 7.7 and 1.2 Hz,ArH), 7.53 (1H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCD₃ 4:1) δ 26.1(CH₃), 27.9 (CH₂), 50.3 (CH₂), 55.3 (CH₂, CH₃O), 61.8 (CH₂), 110.4(CH(Ar)), 123.5 (CH(Ar)), 126.1 (C(Ar)), 126.9 (CH(Ar)), 128.2 (CH(Ar)),128.3 (CH(Ar)), 133.2 (CH(Ar)), 133.7 (C(Ar)), 136.9 (C(Ar)), 137.1(C(Ar)), 138.9 (C(Ar)), 149.6 (C(Ar)), and 197.3 (CO). LC/MS (ES−)t_(r)=1.01 min m/z 389.56 (M⁻−H); MeOH/H₂O 95/5; HPLC t_(r)=4.02 min(96.3%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(4-methoxyphenethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline83

Light yellow powder, 145 mg (75%), mp=140-141° C., R_(f): 0.42 (EtOAc),¹H NMR (270 MHz, CDCl₃) δ 2.70-2.88 (8H, m, 4×CH₂), 3.68 (2H, s, CH₂),3.78 (3H, s, OCH₃), 3.84 (3H, s, OCH₃), 5.10 (2H, br, NH₂), 6.65 (1H, s,ArH), 6.81-6.86 (m, 2H, ArH), 7.08 (1H, s, ArH), 7.11-7.16 (2H, m, ArH),¹³C NMR (67.5 MHz, CDCl₃) δ 28.1 (CH₂), 33.0 (CH₂), 50.6 (CH₂), 55.4(CH₃O), 55.9 (CH₂), 56.4 (CH₃O), 60.2 (CH₂), 111.1 (CH(Ar)), 113.9(2×CH(Ar)), 124.2 (CH(Ar)), 125.9 (C(Ar)), 127.5 (C(Ar)), 129.7(2×CH(Ar)), 132.1 (C(Ar)), 134.5 (C(Ar)), 137.4 (C(Ar)), 149.4 (C(Ar))and 158.1 C(Ar)). LC/MS (ES−) t_(r)=1.13 min m/z 391.57 (M⁻−H); MeOH/H2O95/5. HPLC t_(r)=4.42 min (97.4%). (CH₃CN/H₂O 90/10).

7-Methoxy-2-(pyridin-2-ylmethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline84

White powder, 105 mg (61%) , mp=162-163° C., R_(f): 0.21 (EtOAc/MeOH10:1), ¹H NMR (270 MHz, CDCl₃/CD₃OD10:1) δ 2.63-2.72 (4H, m, 2×CH₂),3.52 (2H, s, CH₂), 3.67 (3H, s, CH₃ O), 3.70 (2H, s, CH₂), 6.49 (1H, s,ArH), 6.96 (1H, s, ArH), 7.14 (1H, ddd, =7.4, 4.9 and 1.0 Hz, PyrH),7.40 (1H, d, J 7.9 Hz, PyrH), 7.62 (1H, dt, J 7.7 and 1.7 Hz, PyrH),8.37 (1H, ddd, J 4.9, 1.7 and 1.0 Hz, PyrH), ¹³C NMR (67.5 MHz,CDCl₃/CD₃OD10:1) δ 27.8 (CH₂), 50.5 (CH₂), 55.6 (CH₂), 55.9 (CH₃O), 63.4(CH₂), 110.8 (CH(Ar)), 122.7 (CHpyr), 123.6 (CHpyr), 123.7 (CH(Ar)),126.5 (C(Ar)), 133.5 (C(Ar)), 137.4 (CHpyr), 137.5 (C(Ar)), 148.5(CHpyr) 149.7 (C(Ar)), and 157.5 (Cpyr). LC/MS (ES−) t_(r)=1.09 min m/z348.51 (M⁺⁻H); MeOH/H₂O 95/5; HPLC t_(r)=3.57 min (100%). (CH₃CN/H₂O90:10)

2-(3-Acetamidobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline85

Light yellow powder, 150 mg (75%), R_(f): 0.18 (EtOAc/MeOH 10:1),mp=124-126° C., ¹H NMR (270 MHz, CDCl₃/CD₃COCDl₃ 5:1) δ 2.06 (3H, s,CH₃), 2.66-2.77 (4H, m, 2×CH₂), 3.52 (2H, s, CH₂), 3.60 (2H, s, CH₂),3.73 (3H, s, CH₃O), 5.89 (2H, br, NH₂), 6.53 (1H, s, ArH), 6.97 (1H, d,J 7.7, 1H, ArH), 7.03 (1H, s, ArH), 7.21 (1H, dd, J 8.2 and 7.7, ArH),7.26-7.30 (1H, m, PyrH), 7.61 (1H, ddd, J 8.2, 2.0, 1.0, ArH). ¹³C NMR(67.5 MHz, CDCl₃/CD₃COCDl₃ 5:1) δ 23.9 (CH₃), 27.3 (CH₂), 50.3 (CH₂),55.4 (CH₂), 56.1 (CH₃O), 62.3 (CH₂), 110.8 (CH(Ar)), 119.5 (CH(Ar)),120.4 (CH(Ar)), 123.8 (CH(Ar)), 125.3 (CH(Ar)), 126.2 (C(Ar)), 129.0(CH(Ar)), 133.0 (C(Ar)), 136.9 (C(Ar)), 137.7 (C(Ar)), 138.7 (C(Ar)),149.8 (C(Ar)) and 169.9 (CO). LC/MS (ES+) t_(r)=3.29 min m/z 406.43(M⁺+H); MeOH/H₂O 50/50 to 95/5 (5 min); HPLC t_(r)=3.67 min (96.3%).(CH₃CN/H₂O 90/10)

7-Methoxy-2-(pyridin-4-ylmethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline86

Light white powder, 135 mg (77%), R_(f): 0.24 (EtOAc/MeOH 10:1), ¹H NMR(270 MHz, CDCl₃/CD₃COCDl₃ 3:1) δ 2.45-2.57 (4H, m, 2×CH₂), 3.32 (2H, s,CH₂), 3.44 (2H, s, CH₂), 3.54 (3H, s, CH₃O), 6.14 (2H, br, NH₂), 6.36(1H, s, ArH), 6.82 (1H, s, ArH), 7.09 (2H, d, J 4.7, 2×PyrH), 8.27 (2H,d, J 4.7, 1.5, PyrH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCDl₃ 3:1) δ 28.1(CH₂), 50.6 (CH₂), 55.6 (CH₂), 55.7 (CH₃O), 61.2 (CH₂), 110.6 (CH(Ar)),123.6 (2×CHpyr), 123.8 (CH(Ar)), 126.3 (C(Ar)), 133.6 (C(Ar)), 137.2(C(Ar)), 147.6 (Cpyr), 149.6 (2×CHpyr) and 149.7 (C(Ar)). LC/MS (ES−)t_(r)=1.04 min m/z 349.38 (M⁺+H); MeOH/H₂O 95/5. HPLC t_(r)=3.46 min(97.1%). (CH₃CN/H₂O 90:10)

2-(3-Acetoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline87

Yellow powder, 170 mg (85%),mp=64-65° C., R_(f): 0.16 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.28 (3H, s, CH₃), 2.70-2.86 (4H, m,2×CH₂), 3.55 (2H, s, CH₂), 3.67 (2H, s, CH₂), 3.81 (3H, s, CH₃O), 4.98(2H, s, NH₂), 6.60 (1H, s, ArH), 6.99 (1H, ddd, J 7.9, 2.2, 1.2, ArH),7.07 (1H, s, ArH), 7.12 (1H, dd, J 2.2, 1.2, ArH), 7.20-7.26 (1H, m,ArH), 7.34 (1H, t, J 7.9, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 21.3 (CH₃),28.3 (CH₂), 50.7 (CH₂), 55.7 (CH₂), 56.4 (CH₃O), 62.2 (CH₂), 111.1(CH(Ar)), 120.5 (CH(Ar)), 122.0 (CH(Ar)), 124.2 (CH(Ar)), 126.4(CH(Ar)), 127.7 (C(Ar)), 129.4 (CH(Ar)), 134.8 (C(Ar)), 137.3 (C(Ar)),140.2 (C(Ar)), 149.3 (C(Ar)), 150.8 (C(Ar)) and 169.8 (CO). LC/MS (ES−)t_(r)=1.02 min m/z 405.17 (M⁺−H); MeOH/H₂O 95/5; HPLC t_(r)=3.96 min(98.57%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(3-(methylsulfonamido)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-ylsulfamate 88

Light yellow powder, 140 mg (63%), mp=151-152° C., R_(f): 0.17 (EtOAc),¹H NMR (270 MHz, CDCl₃/CD₃COCDl₃ 3:1) δ 2.28-2.39 (4H, m, 2×CH₂), 2.56(3H, s, CH₃), 3.15 (2H, s, CH₂), 3.26 (2H, s, CH₂), 3.38 (3H, s, CH₃O),6.17 (2R, br, NH₂), 6.23 (1H, s, ArH), 6.64 (1H, s, ArH), 6.74-6.96 (4H,m, ArH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCDl₃ 3:1) δ 28.0 (CH₂), 38.5(CH₃), 50.2 (CH₂), 55.4 (CH₂ and CH₃O), 61.9 (CH₂), 110.5 (CH(Ar)),118.8 (CH(Ar)), 120.4 (CH(Ar)), 123.5 (CH(Ar)), 124.7 (CH(Ar)), 126.3(C(Ar)), 129.0 (CH(Ar)), 133.9 (C(Ar)), 137.1 (C(Ar)), 137.9 (C(Ar)),139.9 (C(Ar)), 149.6 (C(Ar)). LC/MS (ES−) t_(r)=0.97 min m/z 440.43(M⁻−H); MeOH/H₂O 95/5; HPLC t_(r)=3.32 min (99.0%). (CH₃CN/H₂O 90/10)

2-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline89

Yellow powder, 165 mg (75%), mp=152-153° C., R_(f): 0.15 (Hexane/EtOAc1:5), ¹H NMR (270 MHz, CD₃COCD₃) δ 2.76-2.88 (4H, m, 2×CH₂), 3.70 (2H,s, CH₂), 3.75 (3H, s, CH₃O), 3.86 (3H, s CH₃O), 3.88 (3H, s, CH₃O), 3.93(2H, s, CH₂), 6.66 (1H, s, ArH), 6.69 (2H, br, NH₂), 6.94 (1H, d, J 8.4Hz, ArH), 7.01 (1H, s, ArH), 7.57 (1H, d, J 2.0 Hz, ArH), 7.74 (1H, dd,J 8.4 and 2.0 Hz, ArH), ¹³C NMR (67.5 MHz, CD₃COCD₃) δ 28.2 (CH₂), 51.0(CH₂), 55.5 (CH₂), 55.6 (CH₃O), 55.8 (2×CH₃O), 64.1 (CH₂), 110.4(CH(Ar)), 110.7 (CH(Ar)), 110.8 (CH(Ar)), 123.3 (CH(Ar)), 123.9(CH(Ar)), 126.2 (C(Ar)), 129.2 (C(Ar)), 133.8 (C(Ar)), 137.1 (C(Ar)),149.0 (C(Ar)), 150.1 (C(Ar)), 153.6 (C(Ar)) and 195.1 (CO). LC/MS (ES−)t_(r)=1.02 min m/z 435.44 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.22 min(97.3%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(3,4,5-trimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline90

Yellow powder, 125 mg (57%), mp=143-144° C., R_(f): 0.32 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.70-2.84 (4H, m, 2×CH₂), 3.58 (2H, s, CH₂), 3.61(2H, s, CH₂), 3.81 (3H, s, CH₃O), 3.83 (3H, s, CH₃O), 3.84 (6H, s,CH₃O), 5.10 (2H, br, NH₂), 6.61 (3H, s, ArH), 7.07 (1H, s, ArH), ¹³C NMR(67.5 MHz, CDCl₃) δ 28.1 (CH₂), 50.4 (CH₂), 55.7 (CH₂), 56.2 (2×CH₃O),56.4 (CH₃O), 61.0 (CH₃O), 62.8 (CH₂), 105.7 (2×CH(Ar)), 111.2 (CH(Ar)),124.2 (CH(Ar)), 127.6 (C(Ar)), 133.7 (C(Ar)), 134.6 (C(Ar)), 137.0(C(Ar)), 137.4 (C(Ar)), 149.4 (C(Ar)) and 153.3 (2×C(Ar)). LC/MS (APCI−)t_(r)=0.94 min m/z 437.19 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.63 min(99.5%). (CH₃CN/H₂O 90:10).

7-Methoxy-2-(2,3-dimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline91

Yellow powder, 135 mg (66%), mp=145-146° C., R_(f): 0.41 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.79-2.85 (4H, m, 2×CH₂), 3.66 (2H, s, CH₂), 3.79(2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.83 (3H, s, CH₃O), 3.87 (3H, s,CH₃O), 4.95 (2H, br, NH₂), 6.61 (1H, s, ArH), 6.85-6.89 (1H, m, ArH),7.03-7.07 (3H, m, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.1 (CH₂), 50.4(CH₂), 55.2 (CH₂), 55.7 (CH₂), 55.8 (CH₃O), 56.4 (CH₃O), 61.1 (CH₃O),111.1 (2×CH(Ar)), 111.6 (CH(Ar)), 122.8 (CH(Ar)), 124.1 (CH(Ar)), 127.4(C(Ar)), 132.8 (C(Ar)), 137.4 (C(Ar)), 141.3 (C(Ar)), 147.9 (C(Ar)),149.3 and 152.8 (C(Ar)). LC/MS (APCI−) t_(r)=0.92 min m/z 407.15 (M−H)⁻;MeOH/H2O 95/5; HPLC t_(r)=1.77 min (97.0%). (CH₃CN/H₂O 90/10).

7-Methoxy-2-(3,4-dimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline92

Yellow powder, 140 mg (70%), mp=155-156° C., R_(f): 0.28 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.65-2.82 (4H, m, 2×CH₂), 3.52 (2H, s, CH₂), 3.59(2H, s, CH₂), 3.77 (3H, s, CH₃O), 3.78 (3H, s, CH₃O), 3.79 (3H, s,CH₃O), 6.77 (1H, s, ArH), 6.89 (2H, s, NH₂), 6.91-6.93 (2H, m, ArH),7.00 (1H, s, ArH), 7.04 (1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.4(CH₂), 50.6 (CH₂), 55.2 (CH₃O), 55.3 (CH₃O), 55.4 (CH₃O), 55.6 (CH₂),62.2 (CH₂), 111.0 (CH(Ar)), 111.6 (CH(Ar)), 112.5 CH(Ar)), 121.0(CH(Ar)), 123.7 (CH(Ar)), 126.6 (C(Ar)), 131.3 (C(Ar)), 134.5 (C(Ar)),137.5 (C(Ar)), 148.7 (C(Ar)), 149.5 (C(Ar)) and 150.2 (C(Ar)). LC/MS(APCI−) t_(r)=0.93 min m/z 407.21 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.65min (99.7%). (CH₃CN/H₂O)

7-Methoxy-2-(2,3,4-trimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline93

Yellow powder, 175 mg (79%): mp=79-80° C., R_(f): 0.35 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.71-2.82 (4H, m, 2×CH₂), 3.61 (2H, s, CH₂), 3.65(2H, s, CH₂), 3.80 (3H, s, CH₃O), 3.85 (3H, s, CH₃O), 3.88 (6H, s,2×CH₃O), 6.61 (1H, s, ArH), 6.65 (1H, d, J 8.6 Hz, ArH), 7.05 (1H, s,ArH), 7.06 (1H, d, J 8.6 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.3(CH₂), 50.3 (CH₂), 55.6 (CH₂), 56.0 (CH₃O), 56.1 (CH₂), 56.4 (CH₃O),60.9 (CH₃O), 61.4 (CH₃O), 107.2 (CH(Ar)), 111.2 (CH(Ar)), 123.5 (C(Ar)),124.1 CH(Ar)), 125.2 (CH(Ar)), 127.7 (C(Ar)), 134.8 (C(Ar)), 137.3(C(Ar)), 142.3 (C(Ar)), 149.3 (C(Ar)), 152.7 (C(Ar)) and 153.1 (C(Ar)).LC/MS (APCI−) t_(r)=0.84 min m/z 437.07 (M−H)⁻; MeOH/H₂O 95/5; HPLCt_(r)=1.87 min (99.8%). (CH₃CN/H₂O 90/10).

7-Methoxy-2-(2,5-dimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline94

Yellow powder, 150 mg (74%): mp=138-139° C., R_(f): 0.41 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.73-2.82 (4H, m, 2×CH₂), 3.63 (2H, s, CH₂), 3.68(2H, s, CH₂), 3.76 (3H, s, CH₃O), 3.79 (3H, s, CH₃O), 3.81 (H, s, CH₃O),4.90 (2H, br, NH₂), 6.61 (1H, s, ArH), 6.76 (1H, dd, J 8.8 and 2.9 Hz,ArH), 6.82 (1H, d, J 8.8 Hz, ArH), 7.02 (1H, d, J 2.9 Hz, ArH), 7.06(1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.2 (CH₂), 50.5 (CH₂), 55.7(CH₂), 55.8 (CH₂), 55.9 (CH₃O), 56.3 (CH₃O), 56.4 (CH₃O), 111.2(CH(Ar)), 111.7 (CH(Ar)), 112.6 (CH(Ar)), 116.3 (CH(Ar)), 124.1(CH(Ar)), 127.3 (C(Ar)), 127.8 (C(Ar)), 135.1 (C(Ar)), 137.2 (C(Ar)),149.2 (C(Ar)), 152.1 (C(Ar)) and 153.6 (C(Ar)). LC/MS (APCI−) t_(r)=0.89min m/z 407.02 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.91 min (98.0%).(CH₃CN/H₂O 90/10)

7-Methoxy-2-(2,4,5-trimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline95

Yellow powder, 140 mg (64%): mp=166-167° C., R_(f): 0.16 (EtOAc), ¹H NMR(270 MHz, CDCl₃/CD₃COCD₃ 5/1) δ 2.63-2.74 (4H, m, 2×CH₂), 3.54 (2H, s,CH₂), 3.58 (2H, s, CH₂), 3.74 (6H, s, 2×CH₃O), 3.75 (3H, s, CH₃O), 3.82(H, s, CH₃O), 5.60 (2H, br, NH₂), 6.47 (1H, s, ArH), 6.54 (1H, s, ArH),6.91 (1H, s, ArH), 6.99 (1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃COCD₃5/1) δ 29.8 (CH₂), 49.7 (CH₂), 55.3 (CH₂), 55.8 (CH₂), 56.0 (CH₃O), 56.1(CH₃O), 56.5 (CH₃O), 56.6 (OCH₃), 97.1 (CH(Ar)), 110.0 (CH(Ar)), 110.9(CH(Ar)), 114.2 (C(Ar)), 123.8 (CH(Ar)), 126.4 (C(Ar)), 127.1 (C(Ar)),143.0 (C(Ar)), 145.4 (C(Ar)), 148.6 (C(Ar)), 149.8 (C(Ar)) and 152.2(C(Ar)). LC/MS (APCI−) t_(r)=0.85 min m/z 437.20 (M−H)⁻; MeOH/H₂O 95/5;HPLC t_(r)=1.81 min (98.2%). (CH₃CN/H₂O90/10)

7-Methoxy-2-(3-(triisopropylsilyloxy)benzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline96

A solution of6-hydroxy-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline(200 mg, 0.45 mmol), 2,6-t-butyl-4methylpyridine (205 mg, 1 mmol) andsulfamoyl chloride (1.80 mmol) in DCM (5 mL) was stirred at RT for 60 h.Water (5 mL) and NaHCO₃ (pH8) were added and the organics were extractedwith ethyl acetate. The organic layer was washed with water, brine,dried (MgSO₄), filtered and the solvent evaporated under vacuum. Theresidual oil was purified by flash chromatography (hexane/ethyl acetate4:1 to 3:2) to give a yellow oil that slowly crystallized. Yellowpowder, 100 mg (63%); mp=110-112° C., R_(f): 0.15 (Hexane/EtOAc 3:1), ¹HNMR (270 MHz, CDCl₃) δ 1.08 (18H, d, J 6.9 Hz, (CH₃)₂CHSi), 1.16-1.30(3H, m, (CH₃)₂CHSi), 2.66-2.81 (4H, m, 2×CH₂), 3.54 (2H, s, CH₂), 3.61(2H, s, CH₂), 3.79 (3H, s, CH₃O), 5.02 (2H, br, NH₂), 6.58 (1H, s, ArH),6.78 (1H, ddd, J 7.9, 2.2 and 1.0 Hz, ArH), 6.89-6.94 (2H, m, ArH), 7.05(1H, s, ArH), 7.16 (1H, t, J 7.9 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ12.7((CH₃)₂CHSi), 18.0 ((CH₃)₂CHSi), 28.2 (CH₂), 50.3 (CH₂), 55.7 (CH₂),56.3 (CH₃O), 62.5 (CH₂), 111.1 (CH(Ar)), 118.8 (CH(Ar)), 120.8 (CH(Ar)),121.9 (CH(Ar)), 124.0 (CH(Ar)), 127.7 (C(Ar)), 129.3 (CH(Ar)), 134.9(C(Ar)), 137.3 (C(Ar)), 139.5 (C(Ar)), 149.3 (C(Ar)) and 156.2 (C(Ar)).LC/MS (ES−) t_(r)=2.50 min m/z 519.56 (M⁻−H); MeOH/H₂O) 95/5; HPLCt_(r)=16.55 min (94.55%). (CH₃CN/H₂O 90/10).

2-(3-Hydroxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline97

A solution of7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline(85 mg, 0.16 mmol) in THF (10 mL) was cooled to 0° C. and a 1M solutionTBAF/THF (0.18 mL, 0.18 mmol) was added drop wise. The reaction mixturewas allowed to warm to rt and stirred 1 hour. After addition of water(10 mL), the organics were extracted with ethyl acetate and the organiclayer washed with water, brine, dried (MgSO₄), filtered and concentratedunder reduced pressure. The resulting oil was purified by flashchromatography (hexane/ethyl actetate 3/2 to 1/5) to give 45 mg ofyellow solid that was stirred in diethyl ether/hexane 1:2, filtered anddried. Yellow powder, 38 mg (66%), mp=134-135° C., R_(f): 0.42 (EtOAc),¹H NMR (270 MHz, CD₃COCD₃) δ 2.67-2.81 (4H, m, 2×CH₂), 3.51 (2H, s,CH₂), 3.59 (2H, s, CH₂), 3.78 (3H, s, CH₃O), 6.73 (1H, dd, J 7.9, 2.5,ArH), 6.77 (1H, s, ArH), 6.84 (1H, d, J 7.4 Hz, ArH), 6.88-6.93 (2H, m,ArH, OH), 7.04 (1H, s, ArH), 7.14 (1H, dd, J 7.9 and 7.4 Hz, ArH), ¹³CNMR (67.5 MHz, CD₃COCD₃) δ 28.4 (CH₂), 50.8 (CH₂), 55.4 (CH₃O), 55.6(CH₂), 62.4 (CH₂), 110.9 (CH(Ar)), 114.0 (CH(Ar)), 115.6 (CH(Ar)), 119.9(CH(Ar)), 123.7 (CH(Ar)), 126.5 (C(Ar)), 129.3 (CH(Ar)), 134.5 (C(Ar)),137.5 (C(Ar)), 140.5 (C(Ar)), 150.2 (C(Ar)) and 157.6 (C(Ar)). LC/MS(ES−) t_(r)=1.01 min m/z 363.37 (M⁻−H); MeOH/H₂O 95/5 HPLC t_(r)=3.72min (98.5%). (CH₃CN/H₂O 90/10).

2-(3-Cyanobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline98

134 mg, 83%,yellow oil. Crystallisation from ethyl acetate/hexane toafforded yellow powder (68 mg, 42%). mp 136-138.5° C. ¹H NMR (270 MHz;DMSO-d₆) 2.69-2.76 (4H, m, 2×CH₂), 3.50 (2H, s, CH₂), 3.71 (5H, s, CH₂and OCH₃), 6.82 (1H, s, CH₂), 7.04 (1H, s, CH), 7.57 (1H, t, J=7.7 Hz,CH), 7.71-7.84 (5H, m, 3×CH and NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 28.37(CH₂), 50.80 (CH₂), 55.48 (CH₂), 56.34 (OCH₃), 61.16 (CH₂), 111.67 (CH),111.82 (C), 119.47 (C), 123.32 (CH), 126.34 (C), 130.16 (CH), 131.52(CH), 132.64 (CH), 134.02 (C), 134.20 (C), 137.62 (C), 140.85 (C),150.19 (C). LC/MS (APCI−) t_(r)=3.69 min, m/z 372.54 (M⁺−H). LRMS (CI+)374.2 (M⁺+H, 10%) and 295.2 (M⁺+H—SO₂NH₂, 80%). HRMS (ES+) calcd. forC₁₈H₂₀N₃O₄S (M⁺+H) 374.1169, found 374.1167. HPLC t_(r)=8.94 min (>97%).

2-(4-Cyanobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline99

111 mg, 67%, yellow powder. mp 154-156° C. ¹H NMR (270 MHz; DMSO-d₆)2.68-2.70 (2H, m, CH₂), 2.74-2.78 (2H, m, CH₂), 3.50 (2H, s, CH₂), 3.71(3H, s, OCH₃), 3.80 (3H, s, CH₂), 6.81 (1H, s, CH), 7.04 (1H, s, CH),7.57 (2H, ˜d, J 8.4 Hz, 2×CH), 7.82 (2H, ˜d, J 8.4 Hz, 2×CH), 7.84 (2H,brs, NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 28.38 (CH₂), 50.88 (CH₂), 55.60(CH₂), 56.35 (OCH₃), 61.61 (CH₂), 110.33 (C), 111.65 (CH), 119.51 (C),123.33 (CH), 126.32 (C), 130.03 (2×CH), 132.84 (2×CH), 133.99 (C),137.63 (C), 145.23 (C), 150.19 (C). LC/MS (APCI+) t_(r)=3.74 min, m/z373.86 (M⁺+H). HRMS (ES+) calcd. for C₁₈H₂₀N₃O₄S (M⁺+H) 374.1169, found374.1171. HPLC t_(r)=8.37 min (>98%).

7-Methoxy-2-(3-nitrobenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline100

121 mg, 85%, yellow powder. mp 160.9-164° C. ¹H NMR (270 MHz; DMSO-d₆)2.72-2.77 (4H, m, 2×CH₂), 3.54 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 3.84(2H, s, CH₂), 6.81 (1H,s , CH), 7.05 (1H, s, CH), 7.66 (1H, t, J 7.9 Hz,CH), 7.82-7.85 (3H, m, CH and NH₂), 8.13-8.17 (1H, m, CH), 8.22 (1H,brs, CH). ¹³C NMR (100 MHz; DMSO-d₆) 27.84 (CH), 50.28 (CH), 54.93 (CH),55.82 (OCH₃), 60.50 (CH), 111.15 (CH), 122.14 (CH), 122.83 (CH), 123.03(CH), 125.79 (C), 129.89 (CH), 133.45 (C), 135.41 (CH), 137.12 (C),141.09 (C), 147.93 (C), 149.67 (C). LC/MS (APCI+) t_(r)=4.01 min, m/z394.45 (M⁺+H). HRMS (ES+) calcd. for C₁₇H₁₉N₃O₆SNa (M⁺+Na) 416.0887,found 416.0888. HPLC t_(r)=2.75 min (>99%).

2-(3-Chlorobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline101

95 mg, 45%, yellow powder. mp 124.8-127.8° C. ¹H NMR (270 MHz; DMSO-d₆)2.69 (2H, d, J 4.6 Hz, CH₂), 2.74 (2H, ˜d, J 4.6 Hz, CH₂), 3.49 (2H, s,CH₂), 3.66 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 6.82 (1H, s, CH), 7.04 (1H,s, CH), 7.32-7.42 (4H, m, 4×CH), 7.84 (2H, brs, NH₂). ¹³C NMR (67.5 MHz;DMSO-d₆) 28.42 (CH₂), 50.86 (CH₂), 55.54 (CH₂), 56.35 (OCH₃), 61.49(CH₂), 111.67 (CH), 123.33 (CH), 126.37 (C), 127.58 (CH), 127.88 (C),128.87 (CH), 130.76 (CH), 133.57 (C), 134.10 (C), 137.59 (C), 141.77(C), 150.19 (C). LC/MS (APCI+) t_(r)=4.60 min, m/z 382.93 (M⁺+H). HRMS(ES+) calcd. for C₁₇H₂₀ClN₂O₄S (M⁺+H) 303.0827, found 383.0829. HPLCt_(r)=4.60 min (>98%).

7-Methoxy-2-(3-trifluoromethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline102

60 mg, 71%, yellow powder. mp 109.5-110.1° C. ¹H NMR (400 MHz; DMSO-d₆)2.66-2.69 (2H, m, CH₂), 2.74-2.76 (2H, m, CH₂), 3.35 (2H, s, CH₂), 3.53(2H, s, CH₂), 3.71 (3H, s, OCH₃), 6.82(1H, s, CH), 7.04 (1H, s, CH),7.26-7.28 (1H, m, CH), 7.34 (1H, s, CH), 7.40 (1H, d, J 7.6 Hz, CH),7.49 (1H, t, J 8.0 Hz, CH), 7.84 (2H, brs, NH₂). ¹³C NMR (67.5 MHz;DMSO-d₆) 27.83 (CH₂), 50.18 (CH₂), 55.03 (CH₂), 55.83 (OCH₃), 60.75(CH₂), 111.15 (CH), 119.56 (CH), 120.14 (q, J=254.6 Hz, CF₃), 120.71(CH), 122.82 (CH), 125.83 (C), 127.66 (CH), 130.28 (CH), 133.53 (C),137.11 (C), 141.55 (C), 148.57 (C), 149.70 (C). LC/MS (APCI−) t_(r)=1.07min, m/z 431.02 (M−H)⁻. HPLC t_(r)=1.70 min (>99%).

2-(3-Fluorobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline103

103 mg, 78%, yellow powder. mp 120-124° C. ¹H NMR (270 MHz; DMSO-d₆)2.69 (2H, d, J 5.0 Hz, CH₂), 2.74 (2H, d, J 4.7 Hz, CH₂), 3.50 (2H, s,CH₂), 3.67 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 6.82 (1H, s, CH), 7.04 (1H,s, CH), 7.04-7.22 (3H, m, 3×CH), 7.35-7.43 (1H, m, CH), 7.85 (2H, s,NH₂). ¹³C NMR (100 MHz; DMSO-d₆) 27.8 (CH₂), 50.28 (CH₂), 54.99 (CH₂),55.85 (OCH₃), 60.99 (CH₂), 111.17 (CH), 113.95 (d, J 20.6 Hz, CH),115.24 (d, J 21.4 Hz, CH), 122.83 (CH), 124.77 (CH), 125.83 (C), 130.28(d, J 8.4 Hz, CH), 133.45 (C), 137.15 (C), 141.41 (d, J 6.9 Hz, C),149.72 (C), 162.36 (d, J 241.6 Hz, CF). LC/MS (APCI+) t_(r)=4.26 min,m/z 367.44 (M⁺+H). HPLC t_(r)=4.0 min (>99%). Anal. calc. forC₁₇H₁₉FN₂O₄S: C, 55.73; H, 5.23; N, 7.65. Found: C, 55.5; H, 5.22; N.7.55%.

2-(3-Isopropoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline104

78 mg, 72%, yellow solid. mp 80° C. dec. ¹H NMR (270 MHz; DMSO-d₆) 1.25(6H, d, J 5.9 Hz, 2×CH₃), 2.66 (2H, d, J 4.9 Hz, CH₂), 2.73 (2H, d, J4.9 Hz, CH₂), 3.49 (2H, s, CH₂), 3.60 (2H, s, CH₂), 3.71 (3H, s, OCH₃),4.58 (1H, septet, J 5.9 Hz, CH), 6.79-6.81 (2H, m, 2×CH), 6.88-6.89 (2H,m, 2×CH), 7.03 (1H, s, CH), 7.22 (1H, t, J 8.0 Hz, CH), 7.82 (2H, brs,NH). ¹³C NMR (67.5 MHz; DMSO-d₆) 22.41 (CH₃), 28.47 (CH₂), 50.79 (CH₂),55.71 (CH₂), 56.36 (CH₃), 62.25 (CH₂), 69.43 (CH), 111.64 (CH), 114.60(CH), 116.22 (CH), 121.16 (CH), 123.33 (CH), 126.47 (C), 129.90 (CH),134.28 (C), 137.58 (C), 140.61 (C), 150.19 (C), 158.02 (C). LC/MS(APCI−) t_(r)=0.86 min, m/z 405.07 (M−H)⁻. HPLC t_(r)=0.86 min (>95%).

2-(3-(Methoxycarbonyl)benzyl)-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline104A

(89 mg, 78%) as a yellow solid. mp 145-146° C. dec. ¹H NMR (270 MHz;DMSO-d₆) 2.70-2.76 (4H, m, 2×CH₂), 3.50 (2H, s, CH₂), 3.70 (3H, s,OCH₃), 3.72 (2H, s, CH₂), 3.85 (3H, s, OCH₃), 6.80 (1H, s, CH), 7.04(1H, s, CH), 7.51 (1H, t, J=7.6 Hz, CH), 7.64 (1H, d, J=7.6 Hz, CH),7.83 (2H, brs, NH₂), 7.88 (1H, dt, J=7.6, 1.5 Hz, CH), 7.97 (1H, s, CH).¹³C NMR (67.5 MHz; DMSO-d₆) 28.41 (CH₂), 50.90 (CH₂), 52.73 (OCH₃),55.55 (CH₂), 56.35 (OCH₃), 61.75 (CH₂), 111.68 (CH), 123.34 (CH), 126.36(C), 128.49 (CH), 129.38 (CH), 129.80 (CH), 130.24 (C), 134.08 (C),134.21 (CH), 137.59 (C), 139.85 (C), 150.20 (C), 166.83 (C). LC/MS(APCI−) t_(r)=0.83 min, m/z 405.07 (M−H)⁻. HPLC t_(r)=1.72 min (>97%).

Synthesis of 2-benzoyl-6-benzyloxy-1,2,3,4-tetrahydroisoquinolines

General Method

The appropriate benzoylchloride or bromide (1.8 mmol) was added in aportionwise manner to a solution of6-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline (1.5 mmol) and TEA (0.42mL, 3 mmol) in CHCl₃ (30 mL) and the mixture was stirred for 18 hours atroom temperature. After addition of water (10 mL) the organics wereextracted with ethyl acetate (80 mL), the organic layer was washed withwater, brine, dried (MgSO₄), filtered and evaporated under reducedpressure. The resulting oil/solid was purified by flash chromatography(hexane/ethyl acetate 10:1 to 1:1).

6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline 105

White powder 400 mg (66%), mp=116°117C, R_(f): 0.35 (Hexane/EtOAc 1:1),¹H NMR (270 MHz, CDCl₃) δ 2.81 and 2.91 (2H, br, CH₂), 3.60-3.93 (2H,br, CH₂), 3.79 (6H, s, 2×OCH₃), 4.50 & 4.79 (2H, br, CH₂), 5.04 (2H, s,OCH₂), 6.50 (1H, t, J 2.2 Hz, ArH), 6.54 (2H, br, ArH), 6.76-7.09 (3H,br, ArH), 7.28-7.43 (5H, m, ArH). LC/MS (ES+) t_(r)=1.37 min m/z 404.59(M+H)⁺; MeOH/H₂O 95/5; LC/MS (ES+) t_(r)=1.37 min m/z 426.55 (M⁺+23);MeOH/H₂O 95/5; HPLC t_(r)=1.81 min (98.6%). (CH₃CN/H₂O 90/10)

6-Benzyloxy-7-methoxy-2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline106

White powder, 0.46 g (79%), nip 92-93° C., R_(f): 0.22 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.63 & 2.79 (2H, m, CH₂),3.44 & 3.85 (2H, m, CH₂), 3.72, 3.76, 3.81 & 3.88 (6H, s, 2×CH₃O), 4.34& 4.84 (2H, br, CH₂), 5.11 (2H, s, OCH₂), 6.38-7.46 (11H, m, ArH). LC/MS(APCI+) t_(r)=4.35 min m/z 402.51 (M⁺−H) and t_(r)=4.90 min m/z 404.46(M⁺+H), MeOH/H₂O 50/50 to 95/5, 5 min; HPLC t_(r)=1.98 min (34.6%) andt_(r)=2.18 min (65.4%). (CH₃OH/H₂O 90/10).

6-Benzyloxy-7-methoxy-2-(3-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline107

Thick colorless oil, 0.50 g (83%), R_(f): 0.26 (ethyl acetate/hexane1:1). ¹H NMR (270 MHz, CDCl₃) δ 2.70 & 2.81 (2H, m, CH₂), 3.58 & 3.86(2H, m, CH₂), 3.80 (6H, s, 2×CH₃O), 4.49 & 4.79 (2H, br, CH₂), 5.11 (2H,s, OCH₂), 6.64 & 6.68 (2H, br, ArH), 6.97 (3H, m, ArH), 7.26-7.46 (6H,m, ArH). LC/MS (APCI+) t_(r)=4.69 min m/z 402.45 (M⁺−H) and t_(r)=5.05min m/z 404.46 (M⁺+H); HPLC t_(r)=2.02 min (13.2%) and t_(r)=2.22 min(83.7%). (CH₃OH/H₂O 90/10)

7-Methoxy-2-(4-methoxybenzoyl)-6-benzyloxy-1,2,3,4-tetrahydroisoquinoline108

White powder, 0.52 g (85%), mp 126-127° C., R_(f): 0.31 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.77 (2H, br, CH₂), 3.67(2H, br, CH₂), 3.83 (6H, s, 2×CH₃O), 4.73 (2H, br, CH₂), 5.11 (2H, s,OCH₂), 6.65 (1H, s, ArH), 6.91 (2H, m, ArH), 7.26 -7.45 (8H, s, ArH).LC/MS (APCI+) t_(r)=1.29 min m/z 404.53 (M⁺+H); MeOH/H₂O 50/50 to 95/5,5 min; HPLC t_(r)=2.78 min (96.0%). (CH₃CN/H₂O 90/10); HRMS (ES) calcd.for C₂₅H₂₅NO₄ (MH⁺), 404.1856 found. 404.1858.

6-Benzyloxy-2-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline 109

White powder, 0.58 g (89%), mp 126-127° C., R_(f): 0.28 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.77 (2H, br, CH₂), 3.83(2H, br, CH₂), 3.88 (3H, s, CH₃O), 3.89 (3H, s, CH₃O), 3.90 (3H, s,CH₃O), 4.61 & 4.74 (2H, br, CH₂), 5.11 (2H, s, OCH₂), 6.65 (1H, s, ArH),6.86 (1H, d, J 8.9 Hz, ArH), 7.01 (1H, s, ArH), 7.03 (1H, dd, J 8.9 &2.0 Hz, ArH), 7.23 -7.46 (6H, m, ArH). LC/MS (APCI+) t_(r)=4.28 min m/z432.48 (M⁺−H) and t_(r)=4.64 min m/z 434.50 (M⁺+H), MeOH/H₂O 50/50 to95/5, 5 min; HPLC t_(r)=2.84 min (11.3%). (CH₃CN/H₂O 70/30) andt_(r)=3.29 min (88.7%). (CH₃CN/H₂0 70/30); HRMS (ES) calcd. forC₂₆H₂₈NO₅ (MH⁺), 434.1962 found. 434.1966.

6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline110

White powder, 0.52 g (85%), mp 130-131° C., R_(f): 0.31 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.70 & 2.81 (2H, br,CH₂), 3.58 & 3.92 (2H, br, CH₂), 3.83 (6H, s, 2×CH₃O), 4.49 & 4.78 (2H,br, CH₂), 5.11 (2H, s, OCH₂), 6.42, 6.63-6.68 (2H, br, ArH), 6.50 (1H,t, J 2.2 Hz, ArH), 6.55 (2H, d, J 2.2 Hz, ArH), 7.26 -7.45 (5H, m, ArH).LC/MS (APCI+) t_(r)=5.02 min m/z 434.43 (M⁺+H); MeOH/H₂O 50/50 to 95/5,5 min; HPLC t_(r)=2.35 min (100%). (CH₃CN/H₂O 90/10); HRMS (ES) calcd.for C₂₆H₂₇NO₅ (MH⁺), 434.1962 found. 434.1962

6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline111

White powder, 0.55 g (79%), mp 63-64° C., R_(f): 0.19 (hexane/ethylacetate 1/1), ¹H NMR (270 MHz, CDCl₃) δ 2.80 (2H, br, CH₂), 3.60 & 3.80(2H, br, CH₂), 3.85 (6H, s, CH₃O), 3.86 (6H, s, CH₃O), 4.50 & 4.77 (2H,br, CH₂), 5.12 (2H, s, CH₂), 6.44 & 6.65 (4H, br, ArH), 7.25-7.44 (5H,m, Ph). LC/MS (ES+) t_(r)=1.16 min m/z 496.26 ((M+Na)⁺, 100%), 464.28(M+1)⁺; MeOH/H₂O 95/5; HPLC t_(r)=1.92 min (96. 7%). (CH₃CN/H₂O 90/10)

2-(3-Cyanobenzoyl)-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline112

White powder, 310 mg (52%), mp=156°157 C, R_(f): 0.18 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.70-2.87 (2H, br, CH₂), 3.52-3.57 &3.91-3.95 (2H, br, CH₂), 3.79 & 3.97 (3H, s, OCH₃), 4.46 & 4.80 (2H, br,CH₂), 5.12 (2H, s, OCH2), 6.40-6.68 (2H, br, ArH), 7.27-7.45 (5H, m,ArH), 7.52-7.58 (1H, m, ArH), 7.66-7.75 (3H, m, ArH). LC/MS (ES+)t_(r)=1.16 min m/z 421.54 (M⁺+23); MeOH/H₂O 95/5; HPLC t_(r)=4.36 min(94.3%). (CH₃CN/H₂O 90/10).

2-(4-Cyanobenzoyl)-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline113

White powder to give 300 mg (50%), mp=187°189 C, R_(f): 0.31(Hexane/EtOAc 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68-2.83 (2H, br, CH₂),3.50-3.54 & 3.90-3.95 (2H, br, CH₂), 3.78 & 3.87 (3H, s, OCH₃), 4.42 &4.80 (2H, br, CH₂), 5.12 (2H, s, OCH₂), 6.38-6.68 (2H, br, ArH),7.26-7.44 (5H, m, ArH), 7.53 (2H, dd, J 6.7 & 1.7 Hz, ArH), 7.72 (2H,dd, J 6.7 & 1.7 Hz, ArH). LC/MS (ES+) t_(r)=1.12 min m/z 421.6 (M⁺+23);MeOH/H₂O 95/5; HPLC t_(r)=1.50 min (98.6%). (CH₃CN/H₂O 90/10).

Synthesis of 2-benzoyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolines

General Method:

A solution of 2-benzoyl-6-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline (1mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C (40mg) and stirred under an atmosphere of hydrogen. The reaction wasmonitored by TLC. Upon completion, the resultant suspension was filteredthrough celite, washed with ethyl acetate and then evaporated underreduced pressure. The crude mixture was purified by flash chromatography(hexane/ethyl acetate3:1 to 1:1) and the resulting solid stirred indiethyl ether, filtered and dried under vacuum.

2-(3,5-Dimethoxybenzoyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline 114

White powder, 260 mg (82%), mp=170-171° C., R_(f): 0.32 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CDCl₃) δ 2.69-2.91 (2H, br, CH₂), 3.59 & 3.92(2H, br, CH₂), 3.78 (6H, s, 2×OCH₃), 4.48 & 4.78 (2H, br, CH₂), 5.79(1H, br, ArH), 6.45-7.03 (5H, m, ArH). LC/MS (ES+) t_(r)=1.37 min m/z426.55 (M⁺+23); MeOH/H₂O 95/5; HPLC t_(r)=1.24 min (99.5%). (CH₃CN/H₂O90/10).

6-Hydroxy-7-methoxy-2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline115

White solid: 280 mg (94%), mp=176-177° C., R_(f): 0.27 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68 & 2.82 (2H, br, CH₂), 3.42 & 4.18(2H, br, CH₂), 3.74, 3.76, 3.81 & 3.87 (6H, s, 2×CH₃O), 4.34 & 4.83 (2H,br, CH₂), 5.55 & 5.57 (1H, s, OH), 6.34-6.71 (2H, br, ArH), 6.92 (1H, d,J 8.4 Hz, ArH), 6.98 (1, m, ArH), 7.26 (1H, m, ArH), 7.35 (1H, m, ArH).LC/MS (APCI+) t_(r)=1.14 min m/z 314.42 (M⁺+H). (MeOH/H₂O 95/5); HPLCt_(r)=1.97 min (100%). (MeOH/H₂O 90/10).

6-Hydroxy-7-methoxy-2-(3-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline116

White powder: 215 mg (68%), mp=141-142° C., R_(f): 0.31 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.73 & 2.85 (2H, br, CH₂), 3.59 & 3.94(2H, br, CH₂), 3.78 & 3.87 (6H, s, 2×CH₃O), 4.48 & 4.79 (2H, br, CH₂),5.57 (1H, s, OH), 6.36-6.69 (2H, br, ArH), 6.94-7.01 (3H, m, ArH), 7.32(1H, dd, J 8.8 and 7.4 Hz, ArH). LC/MS (APCI+) t_(r)=1.16 min m/z 314.42(M⁺+H). (MeOH/H₂O 95/5); HPLC t_(r)=1.98 min (100%). (MeOH/H₂O 90/10).

6-Hydroxy-7-methoxy-2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline117

White powder, 280 mg (89%), mp=173-174° C., R_(f): 0.29 (EtOAc/Hexane2:1), ¹H NMR (400 MHz, DMSO-d6) δ 2.68 (2H, t, J 6.9 Hz, CH₂), 3.70 (2H,br, CH₂), 3.80 (6H, s, 2×CH₃O), 4.57 (2H, s, CH₂), 6.55 (1H, s, ArH),6.78 (1H, br, ArH), 7.00 (2H, m, ArH), 7.41 (2H, m, ArH), 8.84 (1H, s,OH). LC/MS (APCI+) t_(r)=0.99 min m/z 314.42 (M⁺+H); MeOH/H₂O 95/5 HPLCt_(r)=4.65 min (100%). (MeOH/H₂O 99/1); HRMS (ES) calcd. for C₁₈H₂₀NO₄(MH⁺), 314.1387 found. 314.1386

2-(3,4-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline118

White powder, 320 mg (94%), mp=132-133° C., R_(f): 0.14 (EtOAc/Hexane2:1), ¹H NMR (400 MHz, CDCl₃) δ 2.80 (2H, br, CH₂), 3.83 (2H, br, CH₂),3.88 (3H, s, CH₃O), 3.90 (6H, s, 2×CH₃O), 4.61 and 4.72 (2H, br, CH₂),5.62 (1H, s, OH), 6.60 (1H, br, ArH), 6.69 (1H, br, ArH), 6.86 (1H, d, J8.9 Hz, ArH), 7.02 (1H, s, ArH), 7.03 (1H, d, J 8.9 Hz, ArH), 8.84 (1H,s, OH). LC/MS (APCI+) t_(r)=0.95 min m/z 344.27 (M⁺+H); MeOH/H₂O 95/5;HPLC t_(r)=1.87 min (100%). (CH₃CN/H₂O 90/10); HRMS (ES) calcd. forC₁₉H₂₂NO₅ (MH⁺), 344.1492 found. 344.1493

2-(3,5-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline119

White powder, 320 mg (94%), mp=139-137° C., R_(f): 0.26 (EtOAc/Hexane2:1), ¹H NMR (400 MHz, CDCl₃) δ 2.73 & 2.84 (2H, br, CH₂), 3.59 & 3.93(2H, br, CH₂), 3.79 (9H, s, 3×CH₃O), 4.48 & 4.77 (2H, br, CH₂), 5.58(1H, s, OH), 6.38 & 6.64 (1H, br, ArH), 6.50 (1H, t, J 2.2 Hz, ArH),6.55 (2H, d, J 2.2 Hz, ArH), 6.68 (1H, br, ArH). LC/MS (APCI+)t_(r)=0.99 min m/z 344.33 (M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=1.93 min(100%). (CH₃CN/H₂O 90/10).

6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline120

White powder, 335 mg (90%), mp 172-173° C., R_(f): 0.71 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 2.79 (2H, br, CH₂), 3.62 & 3.83 (2H, br, CH₂),3.85 (12H, s, CH₃O), 4.50 & 4.76 (2H, br, CH₂), 5.54 (1H, s, OH), 6.41 &6.66 (3H, br, ArH), 6.70 (1H, s, ArH). LC/MS (ES−) t_(r)=0.89 min m/z372.07 (M−1)⁻, 100%); MeOH/H₂O 95/5; HPLC t_(r)=2.10 min (100%).(acetonitrile/water 70/30).

Synthesis of 2-benzoyl-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinolines

General Method:

A solution of 2-benzoyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline (0.5mmol) and sulfamoyl chloride (1 mmol) in DMA (1 mL) was stirred at rtunder nitrogen for 24 hours. After addition of water (5 mL) the organicswere extracted into ethyl acetate (2×50 mL), the organic layers washedwith water and brine, then dried (MgSO₄) and evaporated. The crudeproduct was purified by flash chromatography (hexane/ethyl acetate).

2-(3,5-Dimethoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline121

White powder (120 mg, 60%), mp=169-170° C., R_(f): 0.27 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CD3COCD₃) δ 2.91 (2H, t, J 5.1 Hz, CH₂), 3.66(2H, br, CH₂), 3.81 (6H, s, 2×OCH₃), 4.76 (2H, br, CH₂), 6.56-6.58 (3H,m, ArH), 7.12-7.14 (3H, m, ArH), 7.28 (2H, br, NH₂). LC/MS (ES−)t_(r)=0.95 min m/z 391.44 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.19 min(99.7%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(2-methoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline122

White solid: 140 mg (72%), mp=193-194° C., R_(f): 0.58 (EtOAc), ¹H NMR(270 MHz, CDCl₃/CD₃OD 5:1) δ 2.80 & 2.87 (2H, br, CH₂), 3.38-3.45 (2H,br, CH₂), 3.68, 3.71, 3.76 & 3.82 (6H, s, 2×CH₃O), 3.74 & 4.05 (2H, br,CH₂), 4.81 (2H, s, NH₂), 6.44 & 6.78 (1H, s, ArH), 6.88-6.98 (2H, m,ArH), 7.06-7.11 (1H, s, ArH), 7.15-7.19 (1H, m, ArH), 7.31-7.38 (1H, m,ArH). LC/MS (APCI−) t_(r)=3.31 min m/z 391.49 (M⁺+H). (gradient MeOH/H₂Ofrom 50/50 to 95/5 in 5 min); HPLC t_(r)=2.25 min (100%). (MeOH/H₂O90/10)

7-Methoxy-2-(3-methoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline123

White solid: 130 mg (66%), mp=186-187° C., R_(f): 0.67 (EtOAc), ¹H NMR(270 MHz, CDCl₃/CD₃OD 5:1) δ 2.77-2.87 (2H, br, CH₂), 3.60-3.76 (2H, br,CH₂), 3.80 & 3.86 (6H, s, 2×CH₃O), 4.53 & 4.81 (2H, br, CH₂), 6.50 &6.80 (1H, br, ArH), 6.92-6.98 (3H, m, ArH), 7.12 (1H, br, ArH), 7.32(1H, t, J 8.2 Hz, ArH). LC/MS (APCI−) t_(r)=3.39 min m/z 391.49 (M⁺+H).(gradient MeOH/H₂O from 50/50 to 95/5 in 5 min); HPLC t_(r)=2.20 min(100%). (MeOH/H₂O 90/10)

7-Methoxy-2-(4-methoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline124

White powder, 165 mg (85%), mp 171-172° C., R_(f): 0.65 (EtOAc), ¹H NMR(270 MHz, CDCl₃) δ 2.70 (2H, br, CH₂), 3.53 (2H, br, CH₂), 3.96 (6H, s,2×CH₃O), 4.50 & 4.64 (2H, br, CH₂), 6.61 & 6.69 (1H, br, ArH), 6.81 (2H,m, ArH), 7.01 (1H, s, ArH), 7.27 (2H, m, ArH). LC/MS (APCI+) t_(r)=3.38min m/z 393.38 (M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=1.86 min (100%).(CH₃CN/H₂O 90/10); HRMS (ES) calcd. for C₁₈H₂₀N₂O₆S (MH⁺), 393.1115found. 393.1112

2-(3,4-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamate-1,2,3,4-tetrahydroisoquinoline125

White powder, 160 mg (76%), mp 155-156° C., R_(f): 0.58 (EtOAc), ¹H NMR(270 MHz, CDCl₃/CD₃OD 5:1) δ 2.73 (2H, br, CH₂), 3.59 & 3.72 (2H, br,CH₂), 3.77 (3H, s, CH₃O), 3.79 (6H, s, 2×CH₃O), 4.52 & 4.65 (2H, br,CH₂), 6.61 & 6.70 (1H, br, ArH), 6.80 (1H, d, J 8.2 Hz, ArH), 6.87 (1H,d, J 2.0 Hz, ArH), 6.90 (1H, dd, J 8.2 and 2.0 Hz, ArH), 7.03 (1H, s,ArH). LC/MS (APCI+) t_(r)=3.00 min m/z 423.42 (M⁺+H); MeOH/H₂O 95/5;HPLC t_(r)=1.76 min (100%). (CH₃CN/H₂O 90/10)

2-(3,5-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline126

White powder, 180 mg (85%), mp 170-171° C., R_(f): 0.55 (EtOAc), ¹H NMR(270 MHz, CDCl₃/CD₃OD 5:1) δ 2.70 & 2.80 (2H, t, J 5.3 Hz, CH₂), 3.55 &3.82 (2H, t, J 5.3 Hz, CH₂), 3.63 (s, 2H, NH₂), 3.71 (9H, s, 3×CH₃O),4.46 & 4.72 (2H, br, CH₂), 6.44 (2H, s, ArH), 6.46 & 6.74 (1H, br, ArH),7.05 (1H, br, ArH). LC/MS (APCI+) t_(r)=3.54 min ink 423.35 (M⁺+H);MeOH/H₂O 95/5; HPLC t_(r)=2.47 min (100%). (CH₃CN/H₂O 70/30)

7-methoxy-6-O-sulfamoyl-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline127

White solid, 170 mg (74%), mp 174-175° C., R_(f:) 0.47 (ethyl acetate),¹H NMR (400 MHz, CDCl₃/CD₃COCD₃) δ 2.55 (2H, br, CH₂), 3.41 (2H, br,CH₂), 3.54 (6H, s, 2×CH₃O), 3.57 (6H, s, 2×CH₃O), 4.50 (2H, br, NH₂),6.16 (2H, br, ArH), 6.40-6.50 (3H, s+br, CH and NH₂) and 6.84 (1H, s,ArH). LC/MS (ES−) t_(r)=0.90 min m/z 451.05 ((M−1)⁻, 100%); MeOH/H₂O95/5 ; HPLC t_(r)=1.46 min (99.7%). (acetonitrile/water 70/30)

6-Benzyloxy-2-(benzoyl)-3,4-dihydro-2H-isoquinolin-1-ones

Method 1:

A solution of 6-benzyloxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one(280 mg, 1 mmol) in 5 mL DMF was cooled to 0-5° C. and 60% NaH (60 mg,1.5 mmol) was added portion wise. The suspension was stirred for 1 hourat room temperature and, after addition of benzoyl chloride (1.1 mmol) 4hours at 80° C. The mixture was cooled to RT, water (20 mL) was addedand the organics were extracted with ethyl acetate (2×50 mL). Theorganic layer was washed with water, brine, dried (MgSO₄) and filtered.Ethyl acetate was removed under reduced pressure and the residual oilpurified by flash chromatography (ethyl acetate/hexane 1/8 to 1/2)affording 330 mg (89%) of white powder.

6-Benzyloxy-7-methoxy-2-(4-methoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one128

White powder, 260 mg (63%), mp 151-152° C., R_(f): 0.72 (ethylacetate/hexane 1:3), ¹H NMR (270 MHz, CDCl₃) δ 3.02 (2H, t, J 6.1 Hz,CH₂), 3.83 (3H, s, CH₃O), 3.86 (3H, s, CH₃O), 4.04 (2H, t, J 6.1 Hz,CH₂), 5.23 (2H, s, OCH₂), 6.73 (1H, s, ArH), 6.88 (2H, d, J 8.7 Hz,ArH), 7.30-7.46 (5H, m, ArH). 7.58 (1H, s, ArH), 7.62 (2H, d, J 8.7 Hz,ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 29.7 (CH₂), 44.9 (CH₂), 55.5 (CH₃O),56.2 (CH₃O), 70.9 (OCH₂), 111.3 (CH(Ar)), 111.5 (CH(Ar)), 113.4(2×CH(Ar)), 121.1 (C(Ar)), 127.3 (2×CH(Ar)), 128.3 (CH(Ar)), 128.5(C(Ar)), 128.9 (2×CH(Ar)), 130.9 (2×CH(Ar)), 134.4 (C(Ar)), 136.1(C(Ar)), 148.7 C(Ar)), 152.6 (C(Ar)), 158.3 (C(Ar)), 162.6 (CO) and174.1 (CO). LC/MS (APCI+) t_(r)=4.73 min m/z 418.57 (M⁺+H). (gradientMeOH/H₂O from 50/50 to 95/5 in 5 min); HPLC t_(r)=2.14 min (100%).(CH₃CN/H₂O 90/10); HRMS (ES) calcd. C₂₅H₂₃NO₅for (MO, 418.1649 found.418.1651

6-(Benzyloxy)-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one129

White powder, 135 mg (30%), mp 180-181° C., R_(f): 0.72 (ethylacetate/hexane 1:3), ¹H NMR (270 MHz, CDCl₃) δ 3.02 (2H, t, J 6.2 Hz,CH₂), 3.78 (6H, s, CH₃O), 3.85 (3H, s, CH₃O), 4.06 (2H, t, J 6.2 Hz,CH₂), 5.23 (2H, s, OCH₂Ph), 6.56 (1H, t, J 2.2 Hz, ArH), 6.70 (2H, d, J2.2 Hz, ArH), 6.73 (1H, s, ArH), 7.29-7.46 (5H, m, ArH). 7.56 (1H, s,ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 28.2 (CH₂), 44.6 (CH₂), 55.6 (CH₃O),56.1 (2×CH₃O), 71.0 (OCH₂), 103.4 (CH(Ar)), 105.8 (2×CH(Ar)), 111.4(CH(Ar)) and 111.5 (CH(Ar)), 120.7 (C(Ar)), 127.2 (2×CH(Ar)), 128.2(CH(Ar)), 128.8 (2×CH(Ar)), 134.5 (C(Ar)), 136.0 and 138.7 (C(Ar)),148.8 (C(Ar)), 152.7 (C(Ar)), 160.4 (2×C(Ar)), 165.5 (CO) and 174.5(CO); LC/MS (APCI+) t_(r)=1.29 min m/z 448.54 (M’ +H); (gradientMeOH/H₂O from 50/50 to 95/5 in 5 min; HPLC t_(r)=2.77 min (100%).(CH₃CN/H₂O 90/10); HRMS (Electrospray) calcd. for C₂₆H₂₅NO₆ (MH⁺),448.1755 found. 448.1756.

Method 2:

A mixture of 2-benzoyl-6-(benzyloxy)-1,2,3,4-tetrahydroisoquinoline (1mmol), KMnO₄ (790 mg, 5 mmol) and 18-crown-6 (50 mg, 0.19 mmol) in DCM(20 mL) was stirred at room temperature. The reaction was monitored byTLC. Upon completion, sodium metabisulfite (95 mg, 5 mmol) and 1 mL 2Maqueous HCl were added and the solution stirred for 30 minutes. Thesuspension was filtered through celite and the organics were extractedwith CHCl₃ (2×50 mL). The organic layer was washed with water, brine,dried with MgSO₄, filtered and the solvents were evaporated underreduced pressure. The crude product was purified by flash chromatography(hexane/EtOAc).

6-Benzyloxy-7-methoxy-2-(2-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one130

White powder, 170 mg (40%), mp=163-164° C., R_(f): 0.64 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.98 (2H, t, J 6.2 Hz, CH₂), 3.63 (3H,s, CH₃O), 3.83 (3H, s, CH₃O), 4.19 (2H, t, J 6.2 Hz, CH₂), 5.22 (2H, s,OCH₂), 6.72 (1H, s, ArH), 6.86 (1H, d, J 8.4 Hz, ArH), 7.01 (1H, dt, J8.4 and 0.8 Hz, ArH), 7.28-7.46 (7H, m, ArH), 7.56 (1H, s, ArH), ¹³C NMR(100 MHz, CDCl₃) δ 28.3 (CH₂), 43.4 (CH₂), 55.7 (CH₃O), 56.2 (CH₃O),70.9 (OCH₂), 110.8 (CH(Ar)), 111.2 (CH(Ar)), 111.4 (CH(Ar)), 120.8(CH(Ar)), 121.1 (C(Ar)), 127.3 (2×CH(Ar)), 127.5 (C(Ar)), 128.3(CH(Ar)), 128.5 (CH(Ar)), 128.9 (2×CH(Ar)), 131.5 (CH(Ar)), 134.8(C(Ar)), 136.1 (C(Ar)), 148.7 (C(Ar)), 152.6 (C(Ar)), 155.6 (C(Ar)),165.0 (CO) and 170.8 (CO); LC/MS (ES+) t_(r)=1.22 min m/z 440.49(M⁺+23); MeOH/H₂O 95/5; LC/MS (ES−) t_(r)=1.22 min m/z 416.44 (M−H)−;MeOH/H₂O 95/5; HPLC t_(r)=1.63 min (97.7%). (CH₃CN/H₂O 90/10).

6-Benzyloxy-7-methoxy-2-(3-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one131

White powder, 175 mg (42%), mp=141-143° C., R_(f): 0.47 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.03 (2H, t, J 6.2 Hz, CH₂), 3.81 (3H,s, CH₃O), 3.85 (3H, s, CH₃O), 4.08 (2H, t, J 6.2 Hz, CH₂), 5.23 (2H, s,OCH₂), 6.73 (1H, s, ArH), 7.01 (1H, ddd, J 8.2, 2.7 and 1.2 Hz, ArH),7.11-7.15 (2H, m, ArH), 7.26-7.45 (6H, m, ArH), 7.56 (1H, s, ArH), ¹³CNMR (100 MHz, CDCl₃) δ 28.2 (CH₂), 44.6 (CH₂), 55.5 (CH₃O), 56.2 (CH₃O),71.0 (OCH₂), 111.4 (CH(Ar)), 111.5 (CH(Ar)), 113.2 (CH(Ar)), 117.4(CH(Ar)), 120.4 (CH(Ar)), 120.7 (C(Ar)), 127.3 (2×CH(Ar)), 128.3(CH(Ar)), 128.9 (2×CH(Ar)), 129.2 (CH(Ar)), 134.5 (C(Ar)), 136.1(C(Ar)), 138.0 (C(Ar)), 148.9 (C(Ar)), 152.8 (C(Ar)), 159.4 (C(Ar)),165.6 (CO) and 174.5 (CO). LC/MS (ES+) t_(r)=1.27 min m/z 440.43(M+23)⁺; MeOH/H₂O 95/5; LC/MS (ES−) t_(r)=1.22 min m/z 416.38 (M−H)⁻;MeOH/H₂O 95/5; HPLC t_(r)=1.68 min (90.3%). (CH₃CN/H₂O 90/10).

6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one132

White powder. 125 mg (30%), mp=158-159° C., R_(f): 0.70 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.13 (2H, t, J 6.2 Hz, CH₂), 3.77 (6H,s, CH₃O), 4.08 (2H, t, J 6.2 Hz, CH₂), 5.13 (2H, s, OCH₂), 6.56 (1H, t,J 2.4 Hz, ArH), 6.72 (2H, d, J 2.4 Hz, ArH), 6.83 (1H, d, J 2.4 Hz,ArH), 6.93 (1H, dd, J 8.9 & 2.4 Hz, ArH), 7.30-7.44 (5H, m, ArH), 8.02(1H, d, J 8.9 Hz, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 29.0 (CH₂), 44.4(CH₂), 55.6 (2×CH₃O), 70.3 (OCH₂), 103.5 (CH(Ar)), 106.0 (2×CH(Ar)),113.2 (CH(Ar)), 114.2 (CH(Ar)), 121.1 (C(Ar)), 127.5 (2×CH(Ar)), 128.4(CH(Ar)), 128.8 (2×CH(Ar)), 132.2 (CH(Ar)), 136.1 (C(Ar)), 138.6(C(Ar)), 142.6 (C(Ar)), 160.5 (2×C(Ar)), 163.0 (C(Ar)), 165.8 (C(Ar)),and 174.4 (CO); LC/MS (ES+) t_(r)=1.31 min m/z 418.72 (M⁺+1); MeOH/H2O95/5; HPLC t_(r)=1.79 min (99.1%). (CH3CN/H2O 90/10).

6-(Benzyloxy)-7-methoxy-2-(3,4-dimethoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one133

White powder, 180 mg (40%), mp=200-201° C., R_(f): 0.23 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.04 (2H, t, J 6.2 Hz, CH₂), 3.87 (3H,s, CH₃O), 3.90 (6H, s, 2×OCH₃), 4.04 (2H, t, J 6.2 Hz, CH₂), 5.23 (2H,s, OCH₂), 6.74 (1H, s, ArH), 6.81 (1H, d, J 8.4 Hz, ArH), 7.20 (1H, dd,J 8.4 and 2.0 Hz, ArH), 7.26 (1H, d, J 2.0 Hz, ArH), 7.28-7.46 (5H, m,ArH), 7.58 (1H, s, ArH), ¹³C NMR (100 MHz, CDCl₃) δ 27.5 (CH₂), 44.3(CH₂), 55.2 (CH₃O), 55.3 (CH₃O), 55.4 (CH₃O), 70.2 (OCH₂), 109.2(CH(Ar)), 110.6 (CH(Ar)), 110.7 (CH(Ar)) 110.8 (CH(Ar)), 120.8 (C(Ar)),122.5 (CH(Ar)), 127.2 (2×CH(Ar)) 128.2 (CH(Ar)), 128.5 (C(Ar)), 128.72×CH(Ar)), 134.3 (C(Ar)), 136.0 (C(Ar)), 148.6 (C(Ar)), 148.8 (C(Ar)),152.1 (C(Ar)), 152.6 (C(Ar)), 165.7 (CO) and 174.2 (CO). LC/MS (ES+)t_(r)=1.19 min m/z 470.52 (M+Na)⁺; MeOH/H₂O 95/5 ; HPLC t_(r)=4.49 min(100%). (CH₃CN/H₂O 90/10)

6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one134

White powder, 120 mg (25%), mp 195-196° C., R_(f): 0.56 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.05 (2H, t, J 6.2 Hz, CH₂), 3.83 (6H,s, CH₃O), 3.87 (3H, s), 3.87 (3H, s), 4.05 (2H, t, J 6.2 Hz, CH₂), 5.23(2H, s, CH₂), 6.75 (1H, s, ArH), 6.84 (2H, s, ArH), 7.29-7.46 (5H, m,Ph), 7.56 (1H, s, ArH), ¹³C NMR (100 MHz, CDCl₃) δ 28.2 (CH₂), 45.0(CH₂), 56.2 (CH₃O), 56.3 (2×CH₃O), 61.0 (CH₃O), 71.0 (OCH₂Ph), 105.7(2×CH(Ar)), 111.4 (CH(Ar)), 111.5 (CH(Ar)) 120.7 (C(Ar)), 127.3(2×CH(Ar)), 128.4 (CH(Ar)), 128.9 (2×CH(Ar)) 131.8 (C(Ar)), 134.4(C(Ar)), 136.1 (C(Ar)), 141.1 (C(Ar)), 148.9 (C(Ar)), 152.8 (C(Ar)),152.9 (2×C(Ar)), 165.6 (CO) and 174.4 (CO); LC/MS (ES+) t_(r)=0.97 minm/z 500.18 (M⁺+Na, 100%), 478.20 (M+1); MeOH/H₂O 95/5 ; HPLC t_(r)=1.98and 2.43 min (98.2%). (CH₃CN/H₂O 90/10)

6-Benzyloxy-2-(3-cyanobenzoyl)-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one135

White powder, 130 mg (32%), mp=195-196° C., R_(f): 0.68 (Hexane/Et0Ae1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.05 (2H, t, J 6.2 Hz, CH₂), 3.82 (3H,s, CH₃O), 3.86 (2H, t, J 6.2 Hz, CH₂), 5.24 (2H, s, OCH₂), 6.74 (1H, s,ArH), 7.30-7.45 (5H, m, ArH), 7.49-7.55 (2H, m, ArH), 7.74 (1H, ddd, J7.9, 1.7 and 1.5 Hz, ArH), 7.79 (1H, ddd, J 7.9, 1.7 and 1.2 Hz, ArH),7.82 (1H, d, J 1.5 and 1.2 Hz, ArH), ¹³C NMR (100 MHz, CDCl₃) δ 28.1(CH₂), 44.4 (CH₂), 56.1 (CH₃O), 71.0 (OCH₂), 111.3 (CH(Ar)), 111.4(CH(Ar)) 112.4 (CN), 118.1 (C(Ar)), 120.0 (C(Ar)), 127.1 (2×CH(Ar)),128.2 (CH(Ar)), 127.8 (2×CH(Ar)) 129.0 (CH(Ar)), 131.5 (CH(Ar)), 131.9(CH(Ar)), 134.3 (CH(Ar)), 134.5 (C(Ar)), 135.8 (C(Ar)), 138.0 (C(Ar)),149.0 (C(Ar)), 153.1 (C(Ar)), 165.4 (CO) and 172.1 (CO); LC/MS (ES+)t_(r)=1.21 min m/z 435.58 (M⁺+Na); MeOH/H₂O 95/5; HPLC t_(r)=4.70 min(99.31%). (CH₃CN/H₂O 90/10).

6-(Benzyloxy)-2-(4-cyanobenzoyl)-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one136

White powder, 135 mg (33%), mp=158-159° C., R_(f): 0.62 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.05 (2H, t, J 6.4 Hz, CH₂), 3.85 (3H,s, CH₃O), 4.11 (2H, t, J 6.4 Hz, CH₂), 5.23 (2H, s, OCH₂), 6.74 (1H, s,ArH), 7.30-7.45 (5H, m, ArH), 7.50 (1H, s, ArH), 7.61 (2H, d, J 6.6 Hz,ArH), 7.68 (2H, d, J 6.6 Hz, ArH). ¹³C NMR (100 MHz, CDCl₃) δ 28.1(CH₂), 44.3 (CH₂), 56.2 (CH₃O), 71.0 (OCH₂), 111.4 (CH(Ar)), 111.5(CH(Ar)) 114.5 (CN), 118.3 (C(Ar)), 120.1 (C(Ar)), 127.3 (2×CH(Ar)),128.2 (2×CH(Ar)), 128.4 (CH(Ar)), 128.9 (2×CH(Ar)) 132.0 (2×CH(Ar)),134.7 (2×C(Ar)), 136.0 (C(Ar)), 141.1 (C(Ar)), 149.1 (C(Ar)), 153.3(C(Ar)), 165.4 (CO) and 172.6 (CO) LC/MS (ES+) t_(r)=1.31 min m/z 418.72(M⁺+1); MeOH/H₂O 95/5 ; HPLC t_(r)=1.79 min (99.1%). (CH₃CN/H₂O 90/10).

2-(Benzoyl)-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-ones

General Method:

A solution of 2-benzoyl-6-(benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one(0.5 mmol) in THF (10 mL) and methanol (10 mL) was treated with 10% Pd/C(40 mg) and stirred under an atmosphere of hydrogen. The reaction wasmonitored by TLC. Upon completion, the resultant suspension was filteredthrough celite, washed with ethyl acetate and then evaporated underreduced pressure. The crude mixture was purified by flash chromatography(hexane/ethyl acetate3:1 to 1:1) and the resulting solid wasrecrystalized in ethyl acetate/hexane 5/1.

2-(3,5-Dimethoxybenzoyl)-6-hydroxy-3,4-dihydro-2H-isoquinoline-1-one 137

White powder (165 mg, 100%), mp=178-179° C., R_(f): 0.78 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CD₃COCD₃) δ 3.14 (2H, t, J 6.2 Hz, CH₂), 3.77(6H, s, CH₃O), 4.02 (2H, t, J 6.2 Hz, CH₂), 6.59 (1H, t, J 2.2 Hz, ArH),6.72 (2H, d, J 2.2 Hz, ArH), 6.81 (1H, d, J 2.2 Hz. ArH), 6.83 (1H, dd,J 8.4 & 2.2 Hz, ArH), 7.83 (1H, dd, J 8.9 & 2.4 Hz, ArH), ¹³C NMR (67.5MHz, CD₃COCD₃) δ 28.4 (CH₂), 44.3 (CH₂), 55.0 (2×CH₃O), 102.4 (CH(Ar)),106.2 (2×CH(Ar)), 114.0 (CH(Ar)), 114.8 (CH(Ar)), 119.7 (C(Ar)), 131.6(CH(Ar)), 139.4 (C(Ar)), 143.6 (C(Ar)), 160.6 (2×C(Ar)), 162.7 (C(Ar)),165.0 (C(Ar)), and 173.9 (CO). LC/MS (ES−) t_(r)=1.05 min m/z 326.51(M−H)−; MeOH/H₂O 95/5; HPLC t_(r)=1.24 min (94.7%). (CH₃CN/H₂O 90/10).

6-Hydroxy-7-methoxy-2-(2-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one138

White powder, (150 mg, 92%), mp=199-200° C., R_(f): 0.47 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, DMSO-d₆) δ 2.94 (2H, t, J 6.2 Hz, CH₂), 3.57 (3H,s, CH₃O), 3.74 (3H, s, CH₃O), 4.05 (2H, t, J 6.2 Hz, CH₂), 6.76 (1H, s,ArH), 6.93-7.00 (2H, m, ArH), 7.27 (1H, dd, J 7.4 and 1.7 Hz, ArH), 7.32(1H, s, ArH), 7.34-7.41 (1H, m, ArH), 10.21 (1H, s, OH), ¹³C NMR (67.5MHz, DMSO-d₆) δ 27.8 (CH₂), 43.5 (CH₂), 56.1 (2×CH₃O), 111.7 (CH(Ar)),111.9 (CH(Ar)), 114.5 (CH(Ar)), 119.2 (C(Ar)), 120.8 (CH(Ar)), 128.2(C(Ar)), 128.5 (CH(Ar)), 131.4 (CH(Ar)), 136.1 (C(Ar)), 147.5 (C(Ar)),152.6 (C(Ar)), 155.8 (C(Ar)), 164.7 (CO) and 170.3 (CO). LC/MS (ES−)t_(r)=1.07 min m/z 326.51 (M−H)−; MeOH/H₂O 95/5; HPLC t^(r)=1.28 min(99.7%). (CH₃CN/H₂O 90/10.

6-Hydroxy-7-methoxy-2-(3-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one139

White powder, 125 mg (80%), mp=198-199° C., R_(f): 0.21 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, DMSO-d₆) δ 3.03 (2H, t, J 5.9 Hz, CH₂), 3.75 (3H,s, CH₃O), 3.76 (3H, s, CH₃O), 3.95 (2H, t, J 5.9 Hz, CH₂), 6.77 (1H, s,ArH), 7.05-7.10 (3H, m, ArH), 7.32 (1H, dt, =6.7 and 1.0 Hz, ArH), 7.34(1H, s, ArH), 10.21 (1H, s, OH), ¹³C NMR (100 MHz, DMSO-d₆) δ 27.7(CH₂), 45.0 (CH₂), 55.8 (CH₃O), 56.1 (CH₃O), 111.7 (CH(Ar)), 113.8(CH(Ar)), 114.6. (CH(Ar)), 116.9 (CH(Ar)), 118.9 (C(Ar)), 120.7(CH(Ar)), 129.7 (CH(Ar)), 136.2 (C(Ar)), 138.8 (C(Ar)), 147.5 (C(Ar)),152.7 (C(Ar)), 159.4 (C(Ar)), 165.4 (CO) and 174.2 (CO). LC/MS (ES−)t_(r)=1.08 min m/z 326.58 (M−H)−; MeOH/H₂O 95/5; HPLC t_(r)=1.30 min(99.3%). (CH₃CN/H₂O 90/10)

6-Hydroxy-7-methoxy-2-(4-methoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one140

White powder, 155 mg (96%), mp=224-225° C., R_(f): 0.43 (ethyl acetate),¹H NMR (270 MHz, DMSO-d6) δ 3.01 (2H, t, J 5.7 Hz, CH₂), 3.77 (3H, s,CH₃O), 3.82 (3H, s, CH₃O), 3.90 (2H, t, J 5.7 Hz, CH₂), 6.77 (1H, s,ArH), 6.95 (2H, d, J 8.6 Hz, ArH), 7.36 (1H, s, ArH), 7.55 (2H, d, J 8.6Hz, ArH), 10.19 (1H, br, OH), ¹³C NMR (67.5 MHz, DMSO-d6) δ 27.2 (CH₂),44.8 (CH₂), 55.4 (CH₃O), 55.6 (CH₃O), 111.2 (CH), 113.3 (2×CH(Ar)),114.1 (CH(Ar)), 118.6 (C(Ar)), 128.4 (C(Ar)), 130.7 (2×CH(Ar)), 135.5(C(Ar)), 146.9 (C(Ar)), 152.0 (Ar), 162 (C(Ar)), 165.1 (C(Ar)), 173.6(CO). LC/MS (APCI-+) t_(r)=3.27 min m/z 328.46 (M⁺+H). (gradientMeOH/H₂O from 50/50 to 95/5 in 5 min); HPLC t_(r)=1.90 min (100%).(CH₃CN/H₂O 90/10); HRMS (ES) calcd. for C₂₄H₂₅NO₂ (MH⁺), 328.1179 found.328.1181

2-(3,5-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one141

White powder, 145 mg (81%), mp 198-199° C., R_(f): 0.33 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.05 (2H, t, J 6.2 Hz,CH₂), 3.78 (6H, s, CH₃O), 3.86 (3H, s, CH₃O), 4.07 (2H, t, J 6.2 Hz,CH₂), 6.16 (1H, s, OH), 6.56 (1H, t, J 2.2 Hz, ArH), 6.71 (2H, d, J 2.2Hz, ArH), 6.79 (1H, s, ArH), 7.54 (1H, s, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 28.1 (CH₂), 44.7 (CH₂), 55.6 (2×CH₃O), 56.2 (CH₃O), 103.3(CH(Ar)) and 105.8 (2×CH(Ar)), 111.0 (CH(Ar)) 113.1 (CH(Ar)), 120.1(C(Ar)), 135.4 (C(Ar)), 138.8 (C(Ar)), 146.0 (C(Ar)), 150.8 (C(Ar)),160.2 (2×C(Ar)), 165.5 (C(Ar)) and 174.4 (CO). LC/MS (APCI+) t_(r)=4.12min m/z 358.25 (M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=2.08 min (100%).(CH₃CN/H₂O 90/10)

2-(3,4-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one142

White powder, 155 mg (87%), mp=199-200° C., R_(f): 0.21 (Hexane/EtOAc1:1), ¹H NMR (400 MHz, DMSO-d₆) δ 3.02 (2H, t, J 5.9 Hz, CH₂), 3.75 (3H,s, CH₃O), 3.76 (3H, s, CH₃O), 3.81 (3H, s, CH₃O), 3.90 (2H, t, J 5.9 Hz,CH₂), 6.77 (1H, s, ArH), 6.96 (1H, d, J 9.2 Hz, ArH), 7.15-7.18 (2H, m,ArH), 7.36 (1H, s, ArH), 10.20 (1H, br, OH); ¹³C NMR (67.5 MHz, DMSO-d₆)δ 27.2 (CH₂), 44.9 (CH₂), 55.5 (CH₃O), 55.6 (CH₃O), 55.7 (CH₃O), 110.6(CH(Ar)), 111.2 (CH(Ar)), 111.6 (CH(Ar)), 114.1 (CH(Ar)), 118.6 (C(Ar)),122.6 (CH(Ar)), 128.5 (C(Ar)), 135.5 (C(Ar)), 147.0 (C(Ar)), 148.1(C(Ar)), 151.8 (C(Ar)), 152.1 (C(Ar)), 165.1 (CO) and 173.7 (CO). LC/MS(ES−) t_(r)=1.05 min m/z 356.60 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.22min (100%). (CH₃CN/H₂O 90/10)

6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one143

White powder, 185 mg (96%), mp 175-176° C., R_(f): 0.30 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.07 (2H, t, J 6.4 Hz,CH₂), 3.83 (6H, s, 2×CH₃O), 3.88 (3H, s, CH₃O), 3.89 (3H, s, CH₃O), 4.06(2H, t, J 6.4 Hz, CH₂), 6.18 (1H, s, ArH), 6.80 (1H, s, ArH), 6.85 (2H,s, ArH), 7.55 (1H, s, OH), ¹³C NMR (100 MHz, CDCl₃) δ 28.0 (CH₂), 45.0(CH₂), 56.2 (CH₃O), 56.3 (2×CH₃O), 61.0 (CH₃O), 105.7 (2×CH(Ar)), 111.0(CH(Ar)), 113.2 (CH(Ar)) 120.2 (C(Ar)), 131.9 (C(Ar)), 135.4 (C(Ar)),141.1 (C(Ar)), 146.1 (C(Ar)), 150.8 (C(Ar)), 152.9 (2×C(Ar)), 165.6 (CO)and 174.4 (CO); LC/MS (ES−) t_(r)=0.90 min m/z 386.24 ((M−1)⁻, 100%);MeOH/H₂O 95/5; HPLC t_(r)=1.55inin (99.0%). (CH₃CN/H₂O 90/10)

2-(3-Cyanobenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one144

White powder, 95 mg (59%), mp=197-198° C., R_(f): 0.61 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CD₃COCCD₃) δ 3.14 (2H, t, J 6.2 Hz, CH₂), 3.85(3H, s, CH₃O), 4.08 (2H, t, J 6.2 Hz, CH₂), 6.83 (1H, s, ArH), 7.42 (1H,s, ArH), 7.65 (1H, dd, J 8.2 and 7.6 Hz, ArH), 7.86-7.91 (2H, m, ArH),8.00-8.06 (1H, m, ArH), 8.71 (1, br, OH), ¹³C NMR (67.5 MHz, CD₃COCCD₃)δ 27.4 (CH₂), 44.5 (CH₂), 55.5 (CH₃O), 111.2 (CH(Ar)), 112.0 (CN), 113.9(CH(Ar)) 118.1 (C(Ar)), 119.4 (C(Ar)), 129.3 (CH(Ar)), 131.5 (CH(Ar)),132.2 (CH(Ar)), 133.9 (CH(Ar)), 136.2 (C(Ar)), 139.0 (C(Ar)), 147.0(C(Ar)), 152.1 (C(Ar)), 165.1 (CO) and 172.0 (CO); LC/MS (ES−)t_(r)=1.05 min m/z 321.47 (M−H)−; MeOH/H2O 95/5; HPLC t_(r)=1.23 min(98.61%). (CH3CN/H2O 90/10).

2-(4-Cyanobenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one145

White powder, 150 mg (94%), mp=198-199° C., R_(f): 0.54 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 3.08 (2H, t, J 6.2 Hz, CH₂), 3.87 (3H,s, CH₃O), 4.12 (2H, t, J 6.2 Hz, CH₂), 6.19 (1H, br, OH), 6.81 (1H, s,ArH), 7.49 (1H, s, ArH), 7.63 (2H, d, J 8.2 Hz, ArH), 7.69 (2H, d, J 8.2Hz, ArH), ¹³C NMR (100 MHz, CDCl₃) δ 28.0 (CH₂), 44.3 (CH₂), 56.3(CH₃O), 110.9 (CH(Ar)), 113.2 (CH(Ar)) 114.5 (CN), 118.3 (C(Ar)), 119.6(C(Ar)), 128.2 (CH(Ar)), 132.1 (CH(Ar)), 135.6 (C(Ar)), 141.1 (C(Ar)),146.2 (C(Ar)), 151.2 (C(Ar)), 165.5 (CO) and 172.6 (CO); LC/MS (AP−)t_(r)=1.00 min m/z 320.98 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.49 min(99.2%). (CH₃CN/H₂O 90/10)

2-(Benzoyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-ones

General Method:

A solution of 2-benzoyl-6-hydroxy-3,4-dihydroisoquinoline-1-one (0.3mmol) and sulfamoyl chloride (0.6 mmol) in DMA (1 mL) was stirred at rtunder nitrogen for 24 hours. After addition of water (5 mL) the organicswere extracted into ethyl acetate (2×50 mL), the organic layers washedwith water and brine, then dried (MgSO₄) and evaporated. The crudeproduct was purified by flash chromatography (hexane/ethyl acetate).

2-(3,5-Dimethoxybenzoyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline-1-one146

White powder, 85 mg (67%), mp=183-184° C., R_(f): 0.58 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CD₃COCD₃) δ 3.30 (2H, t, J 6.4 Hz, CH₂), 3.78(6H, s, CH₃O), 4.09 (2H, t, J 6.4 Hz, CH₂), 6.63 (1H, t, J 2.2 Hz, ArH),6.76 (2H, d, J 2.2 Hz, ArH), 7.32 (1H, dd, J 8.8, 2.5 Hz, ArH), 7.38(1H, d, J 2.5 Hz, ArH), 7.39 (2H, s, NH₂), 8.03 (1H, d, J 8.9 Hz, ArH),¹³C NMR (67.5 MHz, CD₃COCD₃) δ 28.1 (CH₂), 44.3 (CH₂), 55.0 (2×CH₃O),102.7 (CH(Ar)), 106.3 (2×CH(Ar)), 120.8 (CH(Ar)), 121.2 (CH(Ar)), 126.6(C(Ar)), 131.1 (CH(Ar)), 138.9 (C(Ar)), 143.4 (C(Ar)), 154.2 (C(Ar)),160.7 (2×C(Ar)), 164.4 (C(Ar)), and 173.7 (CO); LC/MS (ES−) t_(r)=0.99min m/z 405.43 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.19 min (99.7%).(CH₃CN/H₂O 90/10.

2-(4-Methoxybenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one147

White powder, 85 mg (71%), mp 171-172° C., R_(f): 0.66 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃/CD₃OD 5:1) δ 3.10 (2H, t, J6.4 Hz, CH₂), 3.58 (2H, br, NH₂), 3.83 (3H, s, CH₃O), 3.85 (3H, s,CH₃O), 4.03 (2H, t, J 6.4 Hz, CH₂), 6.88 (2H, m, ArH), 7.31 (1H, s,ArH), 7.62 (2H, m, Ph). 7.67 (1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ28.9 (CH₂), 46.5 (CH₂), 56.9 (CH₃O), 57.7 (CH₃O), 114.8 (CH(Ar)), 114.9(CH(Ar)), 115.0 (2×CH(Ar)), 124.3 (CH(Ar)), 128.5 (C(Ar)), 129.2(C(Ar)), 132.5 (2×CH(Ar)), 135.1 (C(Ar)), 144.5 (C(Ar)), 152.5 (C(Ar)),164.4 (C(Ar)), 166.7 (CO), and 176.5 (CO); LC/MS (APCI+) t_(r)=0.96 minm/z 407.42 (M⁺+H). (MeOH/H₂O 95/5); HPLC t_(r)=4.13 min (99.5%).(MeOH/H₂O 99/1); HRMS (ES) calcd. for C₁₈H₁₈N₂O₇S (MH⁺), 407.0907 found.407.0904

7-Methoxy-2-(2-methoxybenzoyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one148

White powder, 90 mg (75%), mp=165-166° C., R_(f): 0.60 (Hexane/EtOAc1:3), ¹H NMR (400 MHz, DMSO-d₆) δ 3.05 (2H, t, J 6.2 Hz, CH₂), 3.60 (3H,s, CH₃O), 3.80 (3H, s, CH₃O), 4.11 (2H, t, J 6.2 Hz, CH₂), 6.96-7.03(2H, m, ArH), 7.31 (1H, dd, J 7.7 and 1.7 Hz, ArH), 7.39 (1H, s, H8),7.34-7.40 (1H, dt, J 8.4, 1.7 Hz, ArH), 7.53 (1H, s, H5), 8.18 (2H, br,NH₂), ¹³C NMR (100 MHz, DMSO-d₆) δ 27.4 (CH₂), 43.4 (CH₂), 56.0 (CH₃O),56.1 (CH₃O), 111.4 (CH(Ar)), 112.4 (CH(Ar)), 120.3 (CH(Ar)), 122.0(CH(Ar)), 126.3 (C(Ar)), 127.2 (C(Ar)), 128.1 (CH(Ar)), 131.2 (CH(Ar)),133.8 (C(Ar)), 142.7 (C(Ar)), 150.6 (C(Ar)), 155.4 (C(Ar)), 163.7 (CO)and 169.9 (CO). LC/MS (ES−) t_(r)=1.00 min m/z 405.50 (M−H)−; MeOH/H₂O95/5; HPLC t_(r)=1.21 min (98.7%). (CH₃CN/H₂O 90/10).

7-Methoxy-2-(3-methoxybenzoyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one149

White powder, 95 mg (77%), mp=173-174° C., R_(f): 0.67 (Hexane/EtOAc1:3), ¹H NMR (400 MHz, DMSO-d₆) δ 3.15 (2H, t, J 5.9 Hz, CH₂), 3.77 (3H,s, CH₃O), 3.81 (3H, s, CH₃O), 4.01 (2H, t, J 5.9 Hz, CH₂), 7.08-7.18(3H, m, ArH), 7.31-7.36 (1H, m, ArH), 7.41 (1H, s, H8), 7.57 (1H, s,ArH), 8.18 (2H, br, NH₂), ¹³C NMR (100 MHz, DMSO-d₆) δ 26.8 (CH₂), 44.4(CH₂), 55.3 (CH₃O), 56.0 (CH₃O), 112.4 (CH(Ar)), 113.4 (CH(Ar)), 116.7(CH(Ar)), 120.3 (CH(Ar)), 122.1 (CH(Ar)), 126.0 (C(Ar)), 127.2 (C(Ar)),129.3 (CH(Ar)), 134.0 (C(Ar)), 137.8 (C(Ar)), 142.9 (C(Ar)), 150.6(C(Ar)), 158.9 (C(Ar)), 164.3 (CO) and 173.7 (CO); LC/MS (ES−)t_(r)=1.01 min m/z 405.43 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.22 min(100%). (CH₃CN/H₂O 90/10.

2-(3,5-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one150

White solid, 105 mg (79%), mp 169-170° C., R_(f): 0.26 (ethylacetate/hexane 1:1), ¹H NMR (270 MHz, CDCl₃/CD₃OD 10:1) δ 2.46 (2H, s,NH₂), 3.08 (2H, t, J 6.2 Hz, CH₂), 3.75 (6H, s, CH₃O), 3.82 (3H, s,CH₃O), 4.05 (2H, t, J 6.2 Hz, CH₂), 6.56 (1H, t, J 2.3 Hz, ArH), 6.68(2H, d, J 2.3 Hz, ArH), 7.29 (1H, s, ArH), 7.65 (1H, s, ArH), ¹³C NMR(67.5 MHz, CDCl₃/CD₃OD 10:1) δ 27.6 (CH₂), 44.6 (CH₂), 55.5 (2×CH₃O),56.4 (CH₃O), 103.7 (CH(Ar)), 105.9 (2×CH(Ar)), 113.1 (CH(Ar)), 122.9(CH(Ar)), 127.0 (C(Ar)), 133.7 (C(Ar)), 138.1 (C(Ar)), 143.1 (C(Ar)),150.9 (C(Ar)), 160.6 (2×C(Ar)), 165.0 (CO) and 174.4 (CO). LC/MS (APCI+)t_(r)=3.86 min m/z 437.39 (M⁺+H). (gradient MeOH/H₂O from 50/50 to 95/5in 5 min); HPLC t_(r)=2.41 min (100%). (CH₃CN/H₂O 90/10).

2-(3,4-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one151

White powder, 100 mg (77%), mp=180-181° C., R_(f): 0.67 (Hexane/EtOAc1:3), ¹H NMR (270 MHz, CD₃COCD₃) δ 3.19 (2H, t, J 6.2 Hz, CH₂), 3.81(3H, s, CH₃O), 3.87 (3H, s, CH₃O), 3.88 (3H, s, CH₃O), 4.03 (2H, t, J6.2 Hz, CH₂), 6.96 (1H, d, J 8.9 Hz, ArH), 7.21 (2H, br, NH₂), 7.28 (1H,s, ArH), 7.30 (1H, d, J 8.9 Hz, ArH), 7.39 (1H, s, ArH), 7.62 (1H, s,ArH), ¹³C NMR (67.5 MHz, CD₃COCD₃) δ 37.4 (CH₂), 45.4 (CH₂), 56.2(2×CH₃O), 56.6 (CH₃O), 111.2 (CH(Ar)), 112.2 (CH(Ar)), 112.9 (CH(Ar)),122.6 (CH(Ar)), 122.4 (CH(Ar)), 126.8 (C(Ar)), 128.5 (C(Ar)), 134.3(C(Ar)), 143.3 (C(Ar)), 148.7 (C(Ar)), 151.1 (C(Ar)), 152.6 (C(Ar)),165.0 (CO) and 174.2 (CO). LC/MS (ES−) t_(r)=1.01 min m/z 435.44 (M−H)⁻;MeOH/H₂O 95/5; HPLC t_(r)=1.18 min (99.6%). (CH₃CN/H₂O 90/10).

7-methoxy-6-O-sulfamoyl-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one152

White powder, 115 mg (82%), mp 196-197° C., R_(f): 0.29 (ethyl acetate),¹H NMR (270 MHz, DMSO) δ 3.16 (2H, t, J 5.7 Hz, CH₂), 3.72 (3H, s,CH₃O), 3.75 (6H, s, 2×CH₃O), 3.81 (3H, s, CH₃O), 3.98 (2H, t, J 5.7 Hz,CH₂), 6.90 (2H, s, ArH), 7.40 (1H, s, ArH), 7.57 (1H, s, ArH), 8.18 (2H,br, NH₂); ¹³C NMR (100 MHz, DMSO) δ 27.2 (CH₂), 45.2 (CH₂), 56.5 (CH₃O),56.7 (2×CH₃O), 56.8 (CH₃O), 106.4 (2×CH(Ar)), 112.9 (CH(Ar)), 122.5(CH(Ar)), 126.7 (C(Ar)), 132.3 (C(Ar)), 134.4 (C(Ar)), 140.9 (C(Ar)),143.3 (C(Ar)), 151.1 (C(Ar)), 153.0 (2×C(Ar)), 164.7 (CO) and 174.1(CO). LC/MS (ES−) t_(r)=0.94 min m/z 465.22 ((M−H)⁻, 100%); MeOH/H₂O95/5 HPLC t_(r)=1.50 min (100%). (CH₃CN/H₂O 90/10).

2-(3-Cyanobenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline-1-one153

White powder (85 mg, 70%), mp=171-172° C., R_(f): 0.60 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CD₃COCCD₃) δ 3.23 (2H, t, J 6.2 Hz, CH₂), 3.88(3H, s, CH₃O), 4.14 (2H, t, J 6.2 Hz, CH₂), 7.24 (2H, br, NH₂), 7.40(1H, s, ArH), 7.58 (1H, s, ArH), 7.69 (1H, dt, J 7.9 and 0.8 Hz, ArH),7.91-7.98 (2H, m, ArH), 8.06 (1H, dt, J 1.8 and 0.8 Hz, ArH), ¹³C NMR(67.5 MHz, CD₃COCCD₃) δ 27.0 (CH₂), 44.5 (CH₂), 55.7 (CH₃O), 112.1 (CN),112.7 (CH(Ar)), 118.0 (C(Ar)), 123.0 (CH(Ar)), 126.8 (C(Ar)), 129.4(CH(Ar)), 131.6 (CH(Ar)), 132.3 (CH(Ar)), 134.2 (CH(Ar)), 134.3 (C(Ar)),138.5 (C(Ar)), 143.4 (C(Ar)), 151.4 (C(Ar)), 165.1 (CO) and 172.0 (CO);LC/MS (ES−) t_(r)=1.00 min m/z 400.53 (M−H)⁻; MeOH/H₂O 95/5; HPLCt_(r)=1.18 min (99.3%). (CH₃CN/H₂O 90/10)

6-O-PG-2-(benzyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-ones

General Method:

A solution of7-methoxy-6-(triisopropylsilyloxy)-3,4-dihydro-2H-isoquinolin-1-one (524mg, 1.5 mmol) or 6-benzyloxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one(425 mg, 1.5 mmol) in dry DMF (5 mL) was cooled to 0° C. and NaH 60%(120 mg, 3 mmol) was added in a portion wise manner. The suspension wasstirred at 0° C. for 30 minutes and methoxybenzylbromide/chloride (1.8mmol) was added in a dropwise manner. The solution was stirred at roomtemperature for 6 hours then a saturated aqueous solution of NH₄Cl (10mL) was added drop wise and the organics were extracted with ethylacetate (80 mL). The organic layer was washed with water, brine, dried(MgSO₄), filtered and evaporated under educed pressure. The resultingoil was purified by flash chromatography (hexane/ethyl acetate 10:1 to5:1).

7-Methoxy-2-(4-methoxybenzyl)-6-(triisopropylsilyloxy)-3,4-dihydro-2H-isoquinolin-1-one154

Colorless oil, 385 mg (55%), R_(f): 0.83 (EtOAc/Hexane 1:1), ¹H NMR (270MHz, CDCl₃) δ 1.07 (18H, d, J 6.9 Hz, (CH₃)₂CHSi), 1.22 (3H, hept, J 6.9Hz, (CH₃)₂CHSi), 2.77 (2H, t, J 6.7 Hz, CH₂), 3.42 (2H, t, J 6.7 Hz,CH₂), 3.78 (3H, s, CH₃O), 3.84 (3H, s, CH₃O), 4.68 (2H, s, NCH₂), 6.60(1H, s, ArH), 6.84 (2H, m, ArH), 7.24 (2H, m, ArH), 7.60 (1H, s, ArH).¹³C NMR (67.5 MHz, CDCl₃) δ 13.0 ((CH₃)₂CHSi), 18.0 (CH₃)₂CHSi), 27.4(CH₂), 45.6 (CH₂), 49.9 (NCH₂), 55.3 (CH₃O), 55.6 (CH₃O), 111.5(CH(Ar)), 113.9 (2×CH(Ar)), 118.5 (CH(Ar)), 122.4 (C(Ar)), 129.5(CH(Ar)), 129.9 (C(Ar)), 131.4 (C(Ar)), 148.8 (C(Ar)), 150.0 (C(Ar)),158.9 (C(Ar)) and 164.8 (CO). LC/MS (APCI+) t_(r)=3.30 min m/z 470.57(M⁺+H); (gradient MeOH/H₂O from 50/50 to 95/5 in 5 min); HPLC t_(r)=8.87min (99.8%). (CH₃CN/H₂O 90/10)

7-Methoxy-2-(3-methoxybenzyl)-6-(3-methoxybenzyloxy)-3,4-dihydro-2H-isoquinolin-1-one155

White powder, 120 mg (18%), mp 85-86° C., R_(f): 0.42 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.77 (2H, t, J 6.6 Hz, CH₂), 3.41 (2H,t, J 6.6 Hz, CH₂), 3.75 (3H, s, CH₃O), 3.77 (3H, s, CH₃O), 3.92 (3H, s,CH₃O), 4.72 (2H, s, CH₂), 5.14 (2H, s, OCH₂), 6.61 (1H, s, ArH),6.76-6.89 (m, 4H, ArH), 6.98 (m, 2H, Ph), 7.21 (2H, t, J 7.9 Hz, ArH),7.25 (t, J 8.1 Hz, 1H, ArH), 7.66 (1H, s, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 27.6 (CH₂), 45.6 (CH₂), 50.4 (CH₂), 55.2 (2×CH₃O), 56.2 (CH₃O),70.8 (OCH₂), 111.2 (CH(Ar)), 111.5 (CH(Ar)), 112.6 (CH(Ar)), 112.8(CH(Ar)), 113.6 (2×CH(Ar)), 118.5 (CH(Ar)), 119.4 (CH(Ar)), and 120.4(CH(Ar)), 122.3 (C(Ar)), 129.7 (CH(Ar)), 129.8 (CH(Ar)), 131.6 (C(Ar)),138.2 (C(Ar)), 139.3 (CH(Ar)), 148.5 (C(Ar)), 151.0 (C(Ar)), 159.9(2×C(Ar)) and 164.7 (CO). LC/MS (APCI+) t_(r)=1.29 min m/z 434.56(M⁺+H); MeOH/H₂O 95/5; HPLC t_(r)=2.25 min (99.9%). (CH₃CN/H₂O 96/4)

7-Methoxy-2-(2-methoxybenzyl)-6-(2-methoxybenzyloxy)-3,4-dihydro-2H-isoquinolin-1-one156

White powder, 350 mg (90%), mp 133-134° C., R_(f): 0.40 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.81 (2H, t, J 6.7 Hz, CH₂), 3.50 (2H,t, J 6.7 Hz, CH₂), 3.83 (3H, s, CH₃O), 3.85 (3H, s, CH₃O), 3.93 (3H, s,CH₃O), 4.78 (2H, s, CH₂), 5.22 (2H, s, OCH₂), 6.64 (1H, s, ArH),6.84-6.95 (m, 4H, ArH), 7.18-7.32 (m, 3H, Ph), 7.44 (dd, J 7.4 and 1.5Hz, 1H, ArH), 7.65 (1H, s, ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 27.9 (CH₂),45.4 (CH₂), 46.3 (NCH₂), 55.4 (2×CH₃O), 56.3 (CH₃O), 65.9 (OCH₂), 110.2(CH(Ar)), 110.3 (CH(Ar)), 111.1 (CH(Ar)), 111.2 (CH(Ar)), 120.7(CH(Ar)), 120.8(CH(Ar)), 122.3 (C(Ar)), 124.9 (C(Ar)), 125.6 (C(Ar)),128.2(CH(Ar)), 128.4(CH(Ar)), 128.9 (CH(Ar)), 129.4 (CH(Ar)), 131.7(C(Ar)), 148.4 (C(Ar)), 151.1 (C(Ar)), 156.5 (C(Ar)), 157.6 (C(Ar)) and164.8 (CO). LC/MS (APCI+) t_(r)=1.40 min m/z 434.56 (M⁺+H); MeOH/H₂O95/5; HPLC t_(r)=2.38 min (99.8%). (CH₃CN/H₂O 96/4).

6-(Benzyloxy)-2-(3,5-dimethoxybenzyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one157

White powder, 440 mg (68%), mp 82-83° C., R_(f): 0.74 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.79 (2H, t, J 6.7 Hz, CH₂), 3.43 (2H,t, J 6.7 Hz, CH₂), 3.75 (6H, s, 2×CH₃O), 3.93 (3H, s, CH₃O), 4.69 (2H,s, CH₂), 5.17 (2H, s, CH₂), 6.35 (1H, t, J 2.5 Hz, ArH), 6.45 (2H, d, J2.5 Hz, ArH), 6.62 (1H, s, ArH), 7.27-7.45 (5H, s, Ph), 7.66 (1H, s,ArH); ¹³C NMR (100 MHz, CDCl₃) δ 27.8 (CH₂), 45.5 (CH₂), 50.5 (CH₂),55.5 (2×CH₃O), 56.3 (CH₃O), 70.9 (CH₂), 99.3 (CH(Ar)), 106.0 (2×CH(Ar)),111.2 (CH(Ar)), 111.5 (CH(Ar)) 122.3 (C(Ar)), 127.3 (2×CH(Ar)), 128.1(CH(Ar)), 128.8 (2×CH(Ar)), 131.6 (C(Ar)), 136.6 (C(Ar)), 140.2 (C(Ar)),148.6 (C(Ar)), 151.0 (C(Ar)), 161.1 (C(Ar)), 164.7 (CO); LC/MS (ES+)t_(r)=1.13 min m/z 456.03 ((M+Na)⁺, 100%), 434.05 (M+H)⁺; MeOH/H₂O 95/5;HPLC t_(r)=2.13 min (100%). (CH₃CN/H₂O 90/10).

6-(benzyloxy)-7-methoxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one158

White powder, 570 mg (82%), mp 136-137° C., R_(f): 0.42 (EtOAc/Hexane1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.80 (2H, t, J 6.8 Hz, CH₂), 3.43 (2H,t, J 6.8 Hz, CH₂), 3.82 (9H, s, 3×CH₃O), 3.93 (3H, s, CH₃O), 4.68 (2H,s, CH₂), 5.17 (2H, s, CH₂), 6.52 (2H, s, ArH), 6.63 (1H, s, ArH),7.26-7.43 (5H, s, Ph), 7.66 (1H, s, ArH); ¹³C NMR (100 MHz, CDCl₃) δ27.8 (CH₂), 45.5 (CH₂), 50.6 (CH₂), 56.3 (3×CH₃O), 61.0 (CH₃O), 70.9(CH₂), 105.0 (2×CH(Ar)), 111.2 (CH(Ar)), 111.5 (CH(Ar)) 122.3 (C(Ar)),127.2 (2×CH(Ar)), 128.1 (CH(Ar)), 128.8 (2×CH(Ar)), 131.5 (C(Ar)), 133.5(C(Ar)), 136.5 (C(Ar)), 137.2 (C(Ar)), 148.6 (C(Ar)), 151.1 (C(Ar)),153.5 (2×C(Ar)), 164.7 (CO); LC/MS (ES+) t_(r)=0.98 min m/z 486.26((M+Na)⁺, 100%), 464.28 (M+H)⁺; MeOH/H₂O 95/5; HPLC t_(r)=1.95 min(99.7%). (CH₃CN/H₂O 90/10)

2-(Benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-ones6-Hydroxy-7-methoxy-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one159

A solution of6-(benzyloxy)-7-methoxy-2-(4-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one(0.24 g, 0.51 mmol) in THF (10 mL) was cooled to 0° C. before 0.61 mL ofa 1M solution of TBAF in THF was added drop wise. The solution wasstirred at rt o/n. After addition of water (5 mL), the organics wasextracted with ethyl acetate and the organic layer was washed withwater, brine, dried (MgSO4), filtered and the solvents evaporated underreduced pressure. The crude product was purified by flash chromatography(hexane/ethyl acetate 4:1 to 2:1) to give 110 mg (69%) of a white solid.mp 171-172° C., R_(f): 0.27 (ethyl acetate/hexane 1:1), ¹H NMR (270 MHz,CDCl₃) δ 2.78 (2H, t, J 6.7 Hz, CH₂), 3.41 (2H, t, J 6.7 Hz, CH₂), 3.77(3H, s, CH₃O), 3.90 (3H, s, CH₃O), 4.69 (2H, s, CH₂), 6.33 (1H, br, OH),6.66 (1H, s, ArH), 6.91 (2H, m, ArH), 7.24 (2H, m, ArH), 7.63 (1H, s,ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 27.5 (CH₂), 45.5 (CH₂), 49.9 (CH₂),55.3 (CH₃O), 56.2 (CH₃O), 110.6 (CH(Ar)), 112.8 (CH(Ar)), 114.0(2×CH(Ar)), 121.5 (C(Ar)), 129.4 (CH(Ar)), 129.7 (C(Ar)), 132.4 (C(Ar)),145.8 (C(Ar)), 149.0 (C(Ar)), 159.0 (C(Ar)) and 164.8 (CO). LC/MS(APCI+) t_(r)=1.00 min m/z 314.42 (M⁺+B); MeOH/H₂O 95/5; HPLC t_(r)=4.27min (>99.99%). (MeOH/H₂O 99/1) HRMS (ES) calcd. for C₁₈H₁₉NO₄ (MH⁺),314.1387 found. 314.1381

6-Hydroxy-7-methoxy-2-(3-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one160

7-methoxy-2-(3 -methoxybenzyl)-6-(3-methoxybenzyloxy)-3,4-dihydro-2H-isoquinolin-1-one (85 mg, 0.196 mmol)was stirred in THF (10 mL) and methanol (10 mL) with 10% Pd/C (20 mg)under hydrogen for 2 hours. After filtration and evaporation of thesolvents under reduced pressure, a yellow solid (70 mg) was obtainedwhich was purified by flash chromatography (hexane/ethyl acetate 1:1) togive 52 mg (76%) of a white solid. mp 181-182° C., R_(f): 0.26(EtOAc/Hexane 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.82 (2H, t, J 6.7 Hz,CH₂), 3.44 (2H, t, J 6.7 Hz, CH₂), 3.77 (3H, s, CH₃O), 3.93 (3H, s,CH₃O), 4.74 (2H, s, CH₂), 6.03 (1H, s, OH), 6.68 (1H, s, ArH), 6.80 (1H,dd, J 7.4 and 1.7 Hz, ArH), 6.84 (1H, d, J 1.7 Hz, Ar), 6.90 (1H, d, J7.7 Hz, ArH), 7.23 (t, J 7.9 Hz, 1H, ArH), 7.64 (1H, s, ArH), ¹³C NMR(67.5 MHz, CDCl₃) δ 27.6 (CH₂), 45.6 (CH₂), 50.4 (CH₂), 55.3 (CH₃O),56.3 (CH₃O), 110.6 (CH(Ar)), 112.7(CH(Ar)), 112.9 (CH(Ar)), 113.6(CH(Ar)), 120.4 (CH(Ar)), 121.7 (C(Ar)), 129.8 (CH(Ar)), 132.5 (C(Ar)),139.4 (C(Ar)), 145.7 (C(Ar)), 148.9 (C(Ar)), 159.9 (C(Ar)) and 164.7(CO). LC/MS (APCI+) t_(r)=4.18 min m/z 314.23 (M⁺+H); (gradient MeOH/H₂Ofrom 50/50 to 95/5 in 5 min); HPLC t_(r)=2.11 min (98.1%). (CH₃CN/H₂O90/10).

6-Hydroxy-7-methoxy-2-(2-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one161

A mixture of7-methoxy-2-(2-methoxybenzyl)-6-(2-methoxybenzyloxy)-3,4-dihydro-2H-isoquinolin-1-one(290 mg, 0.67 mmol) and 10% Pd/C in THF (20 mL) and methanol (20 mL) wasstirred under hydrogen at rt for 4 hours. After filtration over celiteand evaporation under reduced pressure the residual solid was stirred indiethyl ether, filtered and dried under vacuum to give 195 mg (93%) of awhite powder. mp 164-165° C., R_(f): 0.28 (EtOAc/Hexane 1:1), ¹H NMR(270 MHz, CDCl₃) δ 2.83 (2H, t, J 6.7 Hz, CH₂), 3.51 (2H, t, J 6.7 Hz,CH₂), 3.83 (3H, s, CH₃O), 3.92 (3H, s, CH₃O), 4.78 (2H, s, CH₂), 6.02(1H, s, OH), 6.68 (1H, s, ArH), 6.87 (1H, d, J 7.4 Hz, ArH), 6.91 (1H,dd, J 7.4 and 1.0 Hz, ArH), 7.23 (1H, dt, J 7.4 & 1.5 Hz, ArH), 7.30(1H, dd, J 7.9 and 1.5 Hz, ArH), 7.63 (1H, s, ArH). ¹³C NMR (67.5 MHz,CDCl₃) δ 27.7 (CH₂), 45.5 (CH₂), 46.3 (CH₂), 55.5 (CH₃O), 56.3 (CH₃O),110.3 (CH(Ar)), 110.5 (CH(Ar)), 112.7 (CH(Ar)), 120.7 (CH(Ar)), 121.9(C(Ar)), 125.7 (C(Ar)), 128.4 (CH(Ar)), 129.3 (CH(Ar)), 132.6 (C(Ar)),139.4 (C(Ar)), 145.5 (C(Ar)), 148.9 (C(Ar)), 157.6 (C(Ar)) and 164.9(CO). LC/MS (APCI+) t_(r)=4.29 min m/z 314.17 (M⁺+H); (gradient MeOH/H₂Ofrom 50/50 to 95/5 in 5 min); HPLC t_(r)=2.36 min (99.1%). (CH₃CN/H₂O90/10).

2-(3,5-dimethoxybenzyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one162

A mixture of6-benzyloxy-2-(3,5-dimethoxybenzyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one(216 mg, 0.5 mmol) and 10% Pd/C in THF (20 mL) and methanol (20 mL) wasstirred under hydrogen at rt for 4 hours. After filtration over celiteand evaporation under reduced pressure the residual solid was purifiedby flash chromatography (hexane/ethyl acetate) and the resultant solidstirred in diethyl ether, filtered and dried under vacuum to give 155 mg(92%) of a white powder, mp 166-167° C., R_(f): 0.76 (ethyl acetate), ¹HNMR (270 MHz, CDCl₃) δ 2.82 (2H, t, J 6.7 Hz, CH₂), 3.44 (2H, t, J 6.7Hz, CH₂), 3.75 (9H, s, 3×CH₃O), 3.93 (3H, s, CH₃O), 4.70 (2H, s CH₂),6.04 (1H, s, OH), 6.35 (1H, t, J 2.5 Hz, ArH), 6.46 (2H, d, J 2.5 Hz,ArH), 6.68 (1H, s, ArH), 7.63 (1H, s, ArH); ¹³C NMR (100 MHz, CDCl₃) δ27.6 (CH₂), 45.6 (CH₂), 50.5 (CH₂), 55.5 (2×CH₃O), 56.3 (CH₃O), 99.3(CH(Ar)), 105.9 (CH(Ar)), 110.6 (CH(Ar)), 112.7 (CH(Ar)), 121.6 (C(Ar)),132.6 (C(Ar)), 140.2 (C(Ar)), 145.7 (C(Ar)), 148.9 (C(Ar)), 161.1(C(Ar)), 164.8 (CO). LC/MS (ES−) t_(r)=0.94 min m/z 342.09 ((M−H)⁻,100%); MeOH/H₂O 95/5; HPLC t_(r)=1.63 min (100%). (CH₃CN/H₂O 90/10)

6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one163

A mixture of 6-benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihydro -2H-isoquinolin-1 -one (230 mg, 0.5 mmol) and 10% Pd/C in THF(20 mL) and methanol (20 mL) was stirred under hydrogen at RT for 4hours. After filtration over celite and evaporation under reducedpressure the residual solid was purified by flash chromatography(hexane/ethyl acetate) and the resultant solid stirred in diethyl ether,filtered and dried under vacuum to give 160 mg (86%) of a white powder,mp 168-169° C., R_(f): 0.63 (ethyl acetate), ¹H NMR (270 MHz, CDCl₃) δ2.82 (2H, t, J 6.7 Hz, CH₂), 3.44 (2H, t, J 6.7 Hz, CH₂), 3.82 (9H, s,3×CH₃O), 3.92 (3H, s, CH₃O), 4.69 (2H, s, CH₂), 6.08 (1H, br, OH), 6.53(2H, s, ArH), 6.69 (1H, s, ArH), 7.63 (1H, s, ArH); ¹³C NMR (100 MHz,CDCl₃) δ 27.7 (CH₂), 45.5 (CH₂), 50.6 (CH₂), 56.2 (3×CH₃O), 61.0 (CH₃O),104.9 (2×CH(Ar)), 110.5 (CH(Ar)), 112.8 (CH(Ar)) 121.6 (C(Ar)), 132.5(C(Ar)), 133.5 (C(Ar)), 137.2 (C(Ar)), 145.7 (C(Ar)), 149.0 (C(Ar)),153.5 (2×C(Ar)), 164.8 (CO). LC/MS (ES−) t_(r)=0.89 min m/z 372.07((M−H)⁻, 100%); MeOH/H₂O 95/5; HPLC t_(r)=1.56 min (100%). (CH₃CN/H₂O90/10).

2-(Benzyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-ones

General Method:

A solution of 2-benzyl-6-hydroxy-3,4-dihydro-2H-isoquinoline-1-one (0.3mmol) and sulfamoyl chloride (0.6 mmol) in DMA (1 mL) was stirred at rtunder nitrogen for 24 hours. After addition of water (5 mL) the organicswere extracted into ethyl acetate (2×50 mL), the organic layers washedwith water and brine, then dried (MgSO₄) and evaporated. The crudeproduct was purified by flash chromatography (hexane/ethyl acetate) andthe resulting solid stirred in diethyl ether, filtered and dried undervacuum.

7-Methoxy-2-(4-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline164

White solid, 86 mg (73%), mp 159-160° C., R_(f): 0.32 (Hexane/EtOAc1:2), ¹H NMR (270 MHz, CDCl₃/CD₃OD 10:1) δ 2.12 (2H, s, NH2), 2.81 (2H,t, J 6.7 Hz, CH₂), 3.42 (2H, t, J 6.7 Hz, CH₂), 3.76 (3H, s, CH₃O), 3.90(3H, s, CH₃O), 4.67 (2H, s, CH₂), 6.82 (2H, m, ArH), 7.14 (1H, s, ArH),7.21 (2H, m, ArH), 7.72 (1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃/CD₃OD10:1) δ 27.0 (CH₂), 45.3 (CH₂), 50.2 (CH₂), 55.3 (CH₃O), 56.4 (CH₃O),112.8 (CH(Ar)), 114.1 (2×CH(Ar)), 122.7 (CH(Ar)), 128.6 (C(Ar)), 129.0(C(Ar)),129.4 (2×CH(Ar)), 131.3 (C(Ar)), 141.3 (C(Ar)), 150.6 (C(Ar)),159.1 (C(Ar)) and 163.8 (CO); LC/MS (APCI+) t_(r)=0.97 min m/z 393.38(M⁺+H). (MeOH/H₂O 95/5); HPLC t_(r)=1.90 min (100%). (CH₃CN/H₂O 90/10);HRMS (ES) calcd. for C₁₈H₂₀N₂O₆S (MH⁺), 393.1115 found. 393.1117.

7-Methoxy-2-(2-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline165

White solid, 90 mg (77%), mp 142-143° C., R_(f): 0.16 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.86 (2H, t, J 6.7 Hz, CH₂), 3.54 (2H,t, J 6.7 Hz, CH₂), 3.84 (3H, s, CH₃O), 3.93 (3H, s, CH₃O), 4.77 (2H, s,CH₂), 5.16 (2H, s, NH₂), 6.87 (1H, d, J 8.2 Hz, ArH), 6.91 (1H, dt, J7.4 and 1.0 Hz, ArH), 7.14 (1H, s, ArH), 7.21-7.31 (2H, m, ArH), 7.77(1H, s, ArH), ¹³C NMR (67.5 MHz, CDCl₃) δ 27.1 (CH₂), 45.8 (CH₂), 46.1(CH₂), 55.4 (CH₃O), 56.7 (CH₃O), 110.4 (CH(Ar)), 113.0 (CH(Ar)), 120.8(CH(Ar)), 122.8 (CH(Ar)), 125.1 (C(Ar)), 128.8 (CH(Ar)), 129.4 (C(Ar)),129.6 (CH(Ar)), 131.7 (C(Ar)), 141.1 (C(Ar)), 150.4 (C(Ar)), 157.6(C(Ar)) and 163.6 (CO). LC/MS (APCI+) t_(r)=3.99 min m/z 393.45 (M⁺H);(gradient MeOH/H₂O from 50/50 to 95/5 in 5 min); HPLC t_(r)=2.42 min(100%). (CH₃CN/H₂O 90/10).

7-Methoxy-2-(3-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline166

White solid, 80 mg (68%), mp 139-140° C., R_(f): 0.15 (Hexane/EtOAc1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.86 (2H, t, J 6.7 Hz, CH₂), 3.47 (2H,t, J 6.7 Hz, CH₂), 3.78 (3H, s, CH₃O), 3.94 (3H, s, CH₃O), 4.73 (2H, s,CH₂), 5.19 (2H, s, NH₂), 6.79-6.89 (3H, m, ArH), 7.15 (1H, s, ArH), 7.24(1H, dt, J 7.6 and 1.0 Hz, ArH), 7.78 (1H, s, ArH), ¹³C NMR (67.5 MHz,CDCl₃) δ 27.1 (CH₂), 45.8 (CH₂), 50.7 (CH₂), 55.3 (CH₃O), 56.6 (CH₃O),113.0 (CH(Ar)), 113.1 (CH(Ar)), and 113.7 (CH(Ar)), 120.3 (CH(Ar)),122.9 (CH(Ar)), 128.9 (C(Ar)) 129.8 (CH(Ar)), 131.5 (C(Ar)), 138.6(C(Ar)), 141.2 (C(Ar)), 150.6 (C(Ar)), 159.9 (C(Ar)) and 163.6 (CO);LC/MS (APCI+) t_(r)=3.72 min m/z 393.64 (kr +H); (gradient MeOH/H₂O from50/50 to 95/5 in 5 min); HPLC t_(r)=2.27 min (100%). (CH₃CN/H₂O 90/10).

2-(3,5-Dimethoxybenzyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one167

White powder, 98 mg (77%), mp 164-165° C., R_(f:) 0.67 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 2.89 (2H, t, J 6.3 Hz, CH₂), 3.47 (2H, t, J6.3 Hz, CH₂), 3.71 (6H, s, 2×CH₃O), 3.84 (3H, s, CH₃O), 4.64 (2H, s,CH₂), 6.40-6.45 (3H, m, ArH), 7.26 (1H, s, ArH), 7.61 (1H, s, ArH), 8.07(2H, br, NH₂); ¹³C NMR (67.5 MHz, CDCl₃) δ 27.0 (CH₂), 46.0 (CH₂), 50.4(CH₂), 55.7 (CH₃O), 56.5 (2×CH₃O), 99.3 (CH(Ar)), 106.0 (2×CH(Ar)),112.4 (CH(Ar)), 122.3 (2×CH(Ar)) 128.1 (C(Ar)), 131.7 (C(Ar)), 140.5(C(Ar)), 141.8 (C(Ar)), 151.0 (C(Ar)), 161.2 (2×C(Ar)), 163.3 (CO);LC/MS (ES−) t_(r)=0.93 min m/z 421.13 ((M−H)⁻, 100%); MeOH/H₂O 95/5;HPLC t_(r)=1.54 min (100%). (CH₃CN/H₂O 90/10)

7-methoxy-6-O-sulfamoyl-2-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one 168

White powder, 100 mg (74%), mp 201-203° C., R_(f): 0.58 (ethyl acetate),¹H NMR (270 MHz, DMSO-d6) δ 2.90 (2H, t, J 6.6 Hz, CH₂), 3.49 (2H, t, J6.6 Hz, CH₂), 3.63 (3H, s, CH₃O), 3.74 (6H, s, 2×CH₃O), 3.84 (3H, s,CH₃O), 4.64 (2H, s, CH₂), 6.61 (2H, s, ArH), 7.26 (1H, s, ArH), 7.61(1H, s, ArH), 8.08 (2H, br, NH₂); ¹³C NMR (67.5 MHz, DMSO-d6) δ 27.0(CH₂), 45.8 (CH₂), 50.4 (CH₂), 56.4 (2×CH₃O), 56.5 (CH₃O), 56.6 (CH₃O),105.3 (2×CH(Ar)), 112.5 (CH(Ar)), 122.3 (CH(Ar)) 128.2 (C(Ar)), 131.8(C(Ar)), 133.9 (C(Ar)), 137.1 (C(Ar)), 141.8 (C(Ar)), 151.0 (C(Ar)),153.5 (2×C(Ar)), 163.9 (CO); LC/MS (ES−) t_(r)=0.89 min m/z 451.18((M−H)⁻, 100%); MeOH/H₂O 95/5; HPLC t_(r)=2.27 min (99.7%). (CH₃CN/H₂O70/30)

N-Sulfonyl Tetrahydroisoquinolines6-Benzyloxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline169

To a solution of the substituted tetrahydroisoquinoline (300 mg, 1.11mmol) in DCM (10 ml) was added triethylamine (0.19 ml, 1.35 mmol)followed by 3-methoxy sulfonyl chloride (0.19 ml, 1.34 mmol). Thereaction mixture was stirred at rt for 12 h. Saturated aqueous sodiumhydrogen carbonate (30 ml) was added and DCM (30 ml). The layers wereseparated and the aqueous layer extracted with DCM (2×30 ml). Thecombined organic layers were washed with brine (30 ml), dried (MgSO₄)and concentrated in vacuo. Purification (flashmaster: 20 g, 100% Hex to100% EtOAc) afforded the title compound (270 mg, 55%) as a colourlesssolid. mp 124-125° C. ¹H NMR (270 MHz; CDCl₃) 2.76 (2H, t, J 5.8 Hz,CH₂), 3.32 (2H, t, J 5.8 Hz, CH₂), 3.81 (3H, s, OCH₃), 3.83 (3H, s,OCH₃), 4.18 (2H, s CH₂), 5.07 (2H, s, CH₂Ph), 6.52 (1H, s, CH), 6.56(1H, s, CH), 7.09 (1H, dt, J 6.9, 2.7 Hz, CH), 7.28-7.45 (8H, m, phenylCH and 3×CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.38 (CH₂), 43.88 (CH₂), 47.34(CH₂), 55.76 (OCH₃), 56.16 (OCH₃), 71.13 (CH₂Ph), 109.53 (CH), 112.66(CH), 114.16 (CH), 118.98 (CH), 119.87 (CH), 124.03 (C), 125.00 (C),127.33 (2×CH), 127.95 (CH), 128.63 (2×CH), 130.22 (CH), 137.02 (C),137.62 (C), 147.09 (C), 148.47 (C), 159.97 (C). LC/MS (APCI+) t_(r)=5.0min, m/z 440.54 (M⁺+H). HPLC t_(r)=5.09 min, >99%.

6-Benzyloxy-7-methoxy-2-(3-trifluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline170

471 mg, 86%, cream solid. Recrystallisation from EtOH afforded a puresample as a colourless powder. mp 118-120° C. ¹H NMR (270 MHz; CDCl₃)2.76 (2H, t, J 5.9 Hz, CH₂), 3.35 (2H, t, J 5.9 Hz, CH₂), 3.82 (3H, s,OCH₃), 4.20 (2H, s CH₂), 5.07 (2H, s, CH₂Ph), 6.52 (1H, s, CH), 6.56(1H, s, CH), 7.28-7.44 (6H, m, 6×CH), 7.56 (1H, t, J 7.9 Hz, CH), 7.67(1H, brs, CH), 7.74 (1H, dt, J 7 .7, 1.5 Hz, CH). ¹³C NMR (100 MHz;CDCl₃) 28.05 (CH₂), 43.70 (CH₂), 47.11 (CH₂), 56.02 (OCH₃), 70.98(CH₂Ph), 109.33 (CH), 114.01 (CH), 120.15 (CH), 120.23 (q, J 257.7 Hz,CF₃), 123.48 (C), 124.66 (C), 125.06 (CH), 125.76 (CH), 127.19 (CH),127.84 (CH), 128.51 (CH), 130.71 (CH), 136.84 (C), 138.72 (C), 147.07(C), 148.44 (C), 149.29 (app. d, J 1.5 Hz, C). LC/MS (APCI+) t_(r)=5.31min, m/z 494.97 (M⁺+H). HPLC t_(r)=5.40 min (>99%). Anal. Calcd. forC₂₄H₂₂F₃NO₅S: C, 58.41; H, 4.49; N, 2.84. Found: C, 58.4; H, 4.50; N,2.66%.

6-Benzyloxy-7-methoxy-2-(toluene-3-sulfonyl)-1,2,3,4-tetrahydroisoquinoline171

211 mg, 45%,colourless solid. Recrystallisation from EtOH afforded apure sample. mp 144-147° C. ¹H NMR (270 MHz; CDCl₃) 2.41 (3H, s, CH₃),2.77 (2H, t, J=5.9 Hz, CH₂), 3.309 (2H, t, J=5.9 Hz, CH₂), 3.81 (3H, s,OCH₃), 4.16 (2H, s CH₂), 5.07 (2H, s, CH₂Ph), 6.52 (1H, s, CH), 6.56(1H, s, CH), 7.27-7.42 (7H, m, 7×CH), 7.59-7.62 (2H, m, 2×CH). ¹³C NMR(67.5 MHz; CDCl₃) 21.50 (CH₃), 28.40 (CH₂), 43.87 (CH₂), 47.35 (CH₂),56.16 (OCH₃), 71.12 (CH₂Ph), 109.53 (CH), 114.12 (CH), 124.08 (C),124.94 (CH), 125.02 (C), 127.33 (2×CH), 127.95 (CH), 128.08 (CH), 128.64(2×CH), 128.99 (CH), 133.72 (CH), 136.18 (C), 137.02 (C), 139.35 (C),147.05 (C), 148.44 (C). LC/MS (APCI+) t_(r)=5.12 min, m/z 424.46 (M⁺+H).HPLC t_(r)=5.08 min (>99%). Anal. Calcd. for C₂₄H₂₅NO₄S: C, 68.06; H,5.95; N, 3.31. Found: C, 67.8; H, 5.93; N, 3.25%.

6-Benzyloxy-7-methoxy-2-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline172

457 mg, 86%, cream foam. mp 136-138.5° C. ¹H NMR (270 MHz; CDCl₃) 2.756(2H, t, J=5.9 Hz, CH₂), 3.37 (2H, t, J=5.9 Hz, CH₂), 3.82 (3H, s, OCH₃),4.220 (2H, s CH₂), 5.07 (2H, s, CH₂Ph), 6.53 (1H, s, CH), 6.55 (1H, s,CH), 7.28-7.41 (5H, m, 5×CH, phenyl), 7.65 (1H, t, J=7.8 Hz, CH), 7.82(1H, d, J=7.4 Hz, CH), 8.00 (1H, d, J=7.9 Hz, CH), 8.06 (1H, s, CH). ¹³CNMR (100 MHz; CDCl₃) 29.95 (CH₂), 43.70 (CH₂), 47.13 (CH₂), 56.0 (OCH₃),70.96 (CH₂Ph), 109.31 (CH), 114.00 (CH), 123.41 (C), 123.15 (q, J=271.3Hz, CF₃), 124.47 (q, J 3.8 Hz, CH), 124.60 (C), 127.18 (2×CH), 127.83(CH), 128.50 (2×CH), 129.38 (q, J=3.8 Hz, CH), 129.84 (CH), 130.69 (CH),131.70 (q, J=33.5 Hz, C), 136.83 (C), 138.07 (C), 147.09 (C), 148.46(C). ¹⁹F NMR (376 MHz; CDCl₃) −62.74 (CF ₃). LC/MS (APCI+) t_(r)=5.22min, m/z 478.42 (M⁺+H). HPLC t_(r)=5.29 min (>99%). Anal. Calcd. forC₂₄H₂₂F₃NO₄S: C, 60.37; H, 4.64; N, 2.93. Found: C, 60.1; H, 4.65; N,2.88%.

6-Benzyloxy-2-(3-chloro-benzenesulfonyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline173

290 mg, 59%, cream solid. Recrystallisation from EtOH afforded a puresample as a white powder. ¹H NMR (270 MHz; CDCl₃) 2.77 (2H, t, J=5.98Hz, CH₂), 3.34 (2H, t, J=5.9 Hz, CH₂), 3.82 (3H, s, OCH₃), 4.20 (2H, sCH₂), 5.08 (2H, s, CH₂Ph), 6.53 (1H, s, CH), 6.56 (1H, s, CH), 7.26-7.47(6H, m, 6×CH), 7.52-7.56 (1H, m, CH), 7.69 (1H, dt, J=7.7,1.5 Hz, CH),7.80 (1H, t, J=1.7 Hz, CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.27 (CH₂), 43.87(CH₂), 47.30 (CH₂), 55.16 (OCH₃), 71.11 (CH₂Ph), 109.47 (CH), 114.12(CH), 123.69 (C), 124.83 (C), 125.76 (CH), 127.32 (CH), 127.73 (CH),127.97 (CH), 128.65 (CH), 130.47 (CH), 133.02 (CH), 135.44(C), 136.97(C), 138.40 (C), 147.16 (C), 148.53 (C). LC/MS (APCI+) t_(r)=5.25 min,m/z 444.49 (M⁺+H). HPLC t_(r)=5.26 min (>99%). Anal. Calcd. forC₂₃H₂₂ClNO₄S: C, 62.23; H, 4.99; N, 3.16. Found: C, 62.2; H, 5.01; N,3.12%.

2-(3-Cyano-benzenesulfonyl)-6-triisopropylsilyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline174

To a solution of the substituted tetrahydroisoquinoline (300 mg, 0.9mmol) in DCM (10 ml) was added triethylamine (0.14 ml, 0.99 mmol)followed by 3-cyanobenzene sulfonyl chloride (199 mg, 0.99 mmol). Thereaction mixture was stirred at rt for 12 h. Saturated aqueous sodiumhydrogen C(Ar)bonate (30 ml) was added and DCM (30 ml). The layers wereseparated and the aqueous layer extracted with DCM (2×30 ml). Thecombined organic layers were washed with brine (30 ml), dried (MgSO₄)and concentrated in vacuo. The crude material was purified (flashmaster:20 g, 100% hex to 50% hex/50% EtOAc over 20 min then to 100% EtOAc over5 min) to afford the title compound (308 mg, 76%) as a colourless solid.¹H NMR (270 MHz; CDCl₃) 1.04 (18H, d, J=6.7 Hz, 6×CH ₃CH), 1.12-1.32(3H, m, 3×CHCH₃), 2.76 (2H, t, J=5.7 Hz, CH₂), 3.39 (2H, t, J=5.9 Hz,CH₂), 3.73 (3H, s, OCH₃), 4.22 (2H, s CH₂), 6.46 (1H, s, CH), 6.54 (1H,s, CH), 7.64 (1H, td, J=7.9, 0.5 Hz, CH), 7.82-7.86 (1H, m, CH),8.0-8.04 (1H, m, CH), 8.11 (1H, t, J=1.3 Hz, CH). ¹³C NMR (67.5 MHz;CDCl₃) 12.92 (CH), 17.98 (CH₃), 27.87 (CH₂), 43.95 (CH₂), 47.37 (CH₂),55.59 (OCH₃), 109.47 (CH), 113.82 (C), 117.24 (C), 120.33 (CH), 123.24(C), 124.58 (C), 130.23 (CH), 131.22 (CH), 131.48 (CH), 135.88 (CH),138.84 (C), 144.61 (C), 149.85 (C). LC/MS (ES+) t_(r)=2.59 min, m/z343.28 (M⁺−H—SiOiPr₃).

2-(2-Cyano-benzenesulfonyl)-6-triisopropylsilyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline175

280 mg, 63%, colourless solid. ¹H NMR (270 MHz; CDCl₃) 1.05 (18H, d,J=6.7 Hz, 6×CH ₃CH), 1.12-1.26 (3H, m, 3×CHCH₃), 2.78 (2H, t, J=5.9 Hz,CH₂), 3.57 (2H, t, J=5.9 Hz, CH₂), 3.72 (3H, s, OCH₃), 4.39 (2H, s CH₂),6.48 (1H, s, CH), 6.54 (1H, s, CH), 7.63-7.77 (2H, m, 2×CH), 7.83 (1H,dd, J=7.4, 1.7 Hz, CH), 8.09(1H, dd, J=7.8, 1.3 Hz, CH). ¹³C NMR. (67.5MHz; CDCl₃) 12.92 (CH), 18.00 (CH₃), 27.85 (CH₂), 43.86 (CH₂), 47.17(CH₂), 55.59 (OCH₃), 109.60 (CH), 110.96 (C), 116.46 (C), 120.34 (CH),123.65 (C), 124.81 (C), 130.37 (CH), 131.71 (CH), 132.98 (CH), 135.67(CH), 140.98 (C), 144.49 (C), 149.73 (C). LC/MS (ES+) t_(r)=2.45 min,m/z 343.41 (M⁺−H—SiOiPr₃).

7-Methoxy-2-(2-methoxy-benzenesulfonyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline176

332 mg, 73%, cream solid. ¹H NMR (270 MHz; CDCl₃) 1.05 (18H, d, J=6.7Hz, 6×CH₃), 1.13-1.29 (3H, m, 3×CH), 2.57 (2H, t, J=5.6 Hz, CH₂), 3.54(2H, t, J=5.6 Hz, CH₂), 3.69 (3H, s OCH₃), 3.72 (3H, s, OCH₃), 4.41 (2H,s, CH₂), 6.47 (1H, s, CH), 6.53 (1H, s, CH), 6.88-6.92 (1H, m, CH),6.99-7.05 (1H, m, CH), 7.44-7.51 (1H, m, CH), 7.94-7.98 (1H, m, CH).LC/MS (ES+) t_(r)=2.26 min, m/z 504.68 (M⁺−H).

7-Methoxy-2-(4-methoxy-benzenesulfonyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline177

292 mg, 65%, colourless solid. ¹H NMR (270 MHz; CDCl₃) 1.04 (18Hm, d,J=6.8 Hz, 6×CH₃CH), 1.12-1.28 (3H, m, 3×CH), 2.76 (2H, t, J=5.8 Hz,CH₂), 3.28 (2H, t, J=5.8 Hz, CH₂), 3.71 (3H, s, OCH₃), 3.84 (3H, s,OCH₃), 4.13 (2H, s, CH₂), 6.44 (1H, s, CH), 6.54 (1H,s, CH), 6.93-6.98(2H, m, 2×CH), 7.73-7.76 (2H, m, 2×CH). ¹³C NMR (67.5 MHz; CDCl₃) 12.91(3×CH), 17.99 (6×CH₃), 28.11 (CH₂), 43.95 (CH₂), 47.50 (CH₂), 55.59(OCH₃), 55.69 (OCH₃), 109.66 (CH), 114.27 (2×CH), 120.27 (CH), 124.07(C), 124.97 (C), 127.96 (C), 129.91 (2×CH), 144.32 (C), 149.63 (C),163.07 (C). LC/MS (ES+) t_(r)=4.35, m/z 528.67 (M⁺+Na).

7-Methoxy-2-(2-(methoxycarbonyl)benzenesulfonyl)-6-benzyloxy-1,2,3,4-tetrahydroisoquinoline177A

(456 mg, 88%) was obtained as a pale yellow foam. ¹H NMR (270 MHz;CDCl₃) 2.75 (2H, t, J 5.9 Hz, CH₂), 3.47 (2H, t, J 5.9 Hz, CH₂), 3.82(3H, s, OCH₃), 3.91 (3H, s, OCH₃), 4.34 (2H, s, CH₂), 5.08 (2H, s,CH₂Ph), 6.56 (1H, s, CH), 6.57 (1H, s, CH), 7.26-7.62 (5H, m, 5×CH),7.47-7.62 (3H, m, 3×CH), 7.84-7.87 (1H, m, CH). ¹³C NMR (67.5 MHz;CDCl₃) 28.37 (CH₂), 43.62 (CH₂), 46.98 (CH₂), 53.28 (OCH₃), 56.19(OCH₃), 71.12 (CH₂), 109.53 (CH), 114.22 (CH), 124.29 (C), 125.14 (C),127.34 (2×CH), 127.94 (CH), 128.48 (CH), 128.63 (2×CH), 129.08 (CH),130.26 (CH), 132.53 (CH), 133.61 (C), 135.72 (C), 137.05 (C), 147.08(C), 148.47 (C), 168.54 (C). LC/MS (APCI−) t_(r)=0.92 min, m/z 466.29(M−H)⁻. HPLC t_(r)=2.07 min (>98%).

6-Hydroxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline178

Hydrogenolysis afforded the title compound (214 mg, 95%) as a colourlesssolid. mp 168-170° C. ¹H NMR (270 MHz; CDCl₃) 2.79 (2H, t, J=5.9 Hz,CH₂), 3.33 (2H, t, J=5.9 Hz, CH₂), 3.81 (3H, s, OCH₃), 3.83 (3H, s,OCH₃), 4.18 (2H, s, CH₂), 5.49 (1H, s, OH), 6.47 (1H, s, CH), 6.61 (1H,s, CH), 7.09 (1H, dt, J=6.9, 2.5 Hz, CH), 7.31-7.42 (3H, m, 3×CH). ¹³CNMR (67 MHz; CDCl₃) 28.25 (CH₂), 43.93 (CH₂), 47.39 (CH₂), 55.76 (OCH₃),56.07 (OCH₃), 108.35 (CH), 112.68 (CH), 114.33 (CH), 118.96 (CH), 119.87(CH), 122.84 (C), 125.80 (C), 130.22 (CH), 137.64 (C), 144.56 (C),145.41 (C), 159.96 (C). LC/MS (APCI+) t_(r)=3.87 min, m/z 350.53 (M⁺+H).HPLC t_(r)=3.8 min (>98%).

6-Hydroxy-7-methoxy-2-(3-trifluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline179

150 mg, 51%, colourless powder. mp 202-203° C. ¹H NMR (270 MHz; CDCl₃)2.50 (2H, t, J=5.9 Hz, CH), 3.06 (2H, t, J=5.9 Hz, CH₂), 3.53 (3H, s,OCH₃), 3.89 (2H, s, CH₂), 6.23 (1H, s, CH), 6.30 (1H, s, CH), 7.17-7.21(1H, m, CH), 7.33-7.38 (2H, m, 2×CH), 7.49 (1H, d, J=8.2 Hz, CH), 7.83(1H, s, OH). ¹³C NMR (100 MHz; CDCl₃) 27.22 (CH₂), 43.21 (CH₂), 46.58(CH₂), 55.27 (OCH₃), 108.33 (CH), 114.44 (CH), 119.35 (CH), 120.87 (C),124.32 (C), 124.54 (CH), 125.22 (CH), 130.35 (CH), 137.88 (C), 144.69(C), 145.80 (C), 148.52 (C). ¹⁹F NMR (376 MHz; CDCl₃) -53.07 (OCE₃).LC/MS (APCI+) t_(r)=1.09 min, m/z 404.42 (M⁺+H). HRMS (ES+) calcd. forC₁₇H₁₇F₃NO₅S (M⁺+H) 404.0774, found 404.0770. HPLC t_(r)=4.05 min(>98%).

6-Hydroxy-7-methoxy-2-(toluene-3-sulfonyl)-1,2,3,4-tetrahydroisoquinoline180

69 mg, 50%, colourless powder. mp 176-179° C. ¹H NMR (270 MHz; CDCl₃)2.41 (3H, s, CH₃), 2.79 (2H, t, J=5.9 Hz, CH), 3.31 (2H, t, J=5.9 Hz,CH₂), 3.81 (3H, s, OCH₃), 4.16 (2H, s, CH₂), 5.48 (1H, s, OH), 6.48 (1H,s, CH), 6.60 (1H, s, CH), 7.33-7.42 (2H, m, 2×CH), 7.60-7.62 (2H, m,2×CH). ¹³C NMR (67.5 MHz; CDCl₃) 21.50 (CH₃), 28.25 (CH₂), 43.91 (CH₂),47.40 (CH₂), 56.08 (OCH₃), 108.37 (CH), 114.31 (CH), 122.90 (C), 124.94(CH), 125.84 (C), 128.07 (CH), 128.99 (CH), 133.71 (CH), 136.25 (C),139.35 (C), 144.44 (C), 145.38 (C). LC/MS (APCI+) t_(r)=3.94 min, m/z334.46 (M⁺+H). HRMS (ES+) calcd. for C₁₇H₂₀NO₄S (M⁺+H) 334.1108, found334.1111. HPLC t_(r)=3.95 min (>95%).

6-Hydroxy-7-methoxy-2-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline181

300 mg, 93%, colourless powder. mp 178-180° C. ¹H NMR (270 MHz; CDCl₃)2.78 (2H, t, J=5.9 Hz, CH), 3.38 (2H, t, J=5.9 Hz, CH₂), 3.82 (3H, s,OCH₃), 4.23 (2H, s, CH₂), 5.50 (1H, s, OH), 6.49 (1H, s, CH), 6.59 (1H,s, CH), 7.66 (1H, t, J=7.8 Hz, CH), 7.82 (1H, d, J=7.9 Hz, CH), 8.00(1H, d, J=7.7 Hz, CH), 8.06 (1H, s, CH). ¹³C NMR (100 MHz; CDCl₃) 26.95(CH₂), 43.71 (CH₂), 46.99 (CH₂), 55.57 (OCH₃), 110.00 (CH), 115.086(CH), 121.50 (C), 123.39 (q, J=271.4 Hz, CF₃), 123.73 (q, J=3.8 Hz, CH),124.70 (C), 129.94 (q, J=3.8 Hz, CH), 130.01 (q, J=32.8 Hz, C—CF₃),131.10 (CH), 131.44 (CH), 137.73 (C), 145.29 (C), 146.34 (C). ¹⁹F NMR(376 MHz; CDCl₃) −61.31 (CF ₃). LC/MS (APCI+) t_(r)=4.28 min, m/z 388.44(M⁺+H). HPLC t_(r)=3.88 min (>99%). Anal. Calc. for C₁₇H₁₆F₃NO₄S: C,52.71; H, 4.16; N, 3.62. Found: C, 52.4; H, 4.16; N, 3.47%.

2-(3-Chloro-benzenesulfonyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline182

200 mg, 90%, off-white powder. mp 175-178° C. ¹H NMR (270 MHz; CDCl₃)2.79 (2H, t, J=5.7 Hz, CH), 3.35 (2H, t, J=6.0 Hz, CH₂), 3.82 (3H, s,OCH₃), 4.19 (2H, s, CH₂), 5.50 (1H, s, OH), 6.49 (1H, s, CH), 6.61 (1H,s, CH), 7.45 (1H, t, J=7.9 Hz, CH), 7.54 (1H, ddd, J=7.9, 2.0, 1.2 Hz,CH), 7.69 (1H, dt, J=7.7, 1.2 Hz, CH), 7.80 (1H, t, J=2.0 Hz, CH). ¹³CNMR (67.5 MHz; CDCl₃) 28.14 (CH₂), 43.91 (CH₂), 47.36 (CH₂), 56.09(OCH₃), 108.32 (CH), 114.36 (CH), 122.53 (C), 125.67 (C), 125.75 (CH),127.73 (CH), 130.46 (CH), 133.01 (CH), 135.42 (C), 138.47 (C), 144.57(C), 145.47 (C). LC/MS (APCI+) t_(r)=4.24 min, m/z 354.44 (M⁺+H). HRMS(ES+) calcd. for C₁₆H₁₇ClNO₄S (M⁺+H) 354.0561, found 354.0562. HPLCt_(r)=3.89 min (>96%).

Desilylations2-(2-Cyano-benzenesulfonyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline183

Silyl deprotection as described above. 188 mg, 91%, cream solid.mp=164-167° C. ¹H NMR (270 MHz; CDCl₃) 2.80 (2H, t, J=5.9 Hz, CH₂), 3.55(2H, t, J=5.9 Hz, CH₂), 3.82 (3H, s, OCH₃), 4.41 (2H, s, CH₂), 5.52 (1H,s, OH), 6.52 (1H, s, CH), 6.60 (1H, s, CH), 7.63-7.77 (2H, m, 2×CH),7.84 (1H, dd, J=7.4, 1.5 Hz, CH), 8.09 (1H, dd, J=7.7, 1.2 Hz, CH). ¹³CNMR (100 MHz; CDCl₃) 27.83 (CH₂), 43.62 (CH₂), 47.0 (CH₂), 55.98 (OCH₃),108.28 (CH), 110.77 (C), 114.28 (CH), 116.27 (C), 122.52 (C), 125.56(C), 130.23 (CH), 132.65 (CH), 132.88 (CH), 135.55 (CH), 140.95 (C),144.47 (C), 145.36 (C). LC/MS (ES−) t_(r)=0.93 min, m/z 343 .28 (M⁺−H).HPLC t_(r)=3.77 min (>99%). Anal. Calc. for C₁₇H₁₆N₂O₄S: C, 59.12; H,4.96; N, 8.11. Found: C, 59.1; H, 4.69; N, 7.89%.

6-Hydroxy-7-methoxy-2-(2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline184

The corresponding silyl compound (332 mg, 0.66 mmol) was desilylatedfollowing the method described above to afford the title compound (103mg, 45%) as a colourless foam. mp 140-142° C. ¹H NMR (270 MHz; CDCl₃)2.62 (2H, t, J=5.9 Hz, CH₂), 3.55 (2H, t, J=5.9 Hz, CH₂), 3.71 (3H, s,OCH₃), 3.82 (3H, s, OCH₃), 4.41 (2H, s, CH₂), 5.46 (1H, s, OH), 6.49(1H, s, CH), 6.61 (1H, s, CH), 6.92 (1H, d, J=8.2 Hz, CH), 7.03 (1H, td,J=7.7, 1.0 Hz, CH), 746-7.51 (1H, m, CH), 7.96 (1H, dd, J=7.7, 1.7 Hz,CH). ¹³C NMR (100 MHz; CDCl₃) 28.05 (CH₂), 43.78 (CH₂), 46.79 (CH₂),55.70 (OCH₃), 56.00 (OCH₃), 108.09 (CH), 111.10 (CH), 114.38 (CH),120.28 (CH), 123.99 (C), 126.37 (C), 127.15 (C), 131.73 (CH), 134.42(CH), 144.14 (C), 145.25 (C), 156.91 (C). LC/MS (ES-) t_(r)=1.02 min,m/z 348.27 (M−H)⁻. HPLC t_(r)=1.35 min (>99%).

6-Hydroxy-7-methoxy-2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline185

177 mg, 95%, colourless solid after recrystallisation from hexane/DCM.mp 147-149° C. ¹H NMR (270 MHz; CDCl₃) 2.79 (2H, t, J=5.9 Hz, CH₂), 3.29(2H, t, J=5.9 Hz, CH₂), 3.82 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 4.14(2H, s, CH₂), 5.46 (1H, s, OH), 6.47 (1H, s, CH), 6.61 (1H, s, CH),6.95-6.98 (2H, m, 2×CH), 7.73-7.76 (2H, m, 2×CH). ¹³C NMR (67.5 MHz;CDCl₃) 28.26 (CH₂), 43.88 (CH₂), 47.43 (CH₂), 55.72 (OCH₃), 56.07(OCH₃), 108.41 (CH), 114.29 (2×CH), 122.94 (C), 125.83 (C), 127.97 (C),129.90 (2×CH), 144.43 (C), 145.40 (C), 163.09 (C). LC/MS (ES−)t_(r)=1.03 min, m/z 348.48 (M−H)⁻. HPLC t_(r)=1.32 min (>99%).

2-(3-Cyano-benzenesulfonyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline186

99.5 mg, 75%, yellow solid. mp 204-206° C. ¹H NMR (270 MHz; CDC₃) 2.78(2H, t, J=5.9 Hz, CH₂), 3.39 (2H, t, 5.9 Hz, CH₂), 3.84 (3H, s, CH₃),4.23 (2H, s, CH₂), 5.50 (1H, s, OH), 6.50 (1H, s, CH), 6.60 (1H,s, CH),7.65 (1H, t, J=7.9 Hz, CH), 7.84 (1H, dt, J=7.9, 1.4 Hz, CH), 8.03 (1H,dt, J=7.9, 1.4 Hz, CH), 8.09 (1H, t, J=1.5 Hz, CH). ¹³C NMR (67.5 MHz;CDCl₃) 27.91 (CH₂), 43.90 (CH₂), 47.37 (CH₂), 56.09 (CH₃), 108.39 (CH),113.75 (C), 114.57 (CH), 117.22 (C), 122.01 (C), 125.34 (C), 130.26(CH), 131.19 (CH), 131.46 (CH), 135.92 (CH), 138.83 (C), 144.87 (C),145.79 (C). LC/MS (ES−) t_(r)=1.01 min, m/z 343.15 (M⁺−H). HPLCt_(r)=3.68 min (>99%). Anal. Calc. for C₁₇H₁₆N₂O₄S: C 59.29, H 4.68, N8.13. Found: C 59.2, H 4.71, N 8.08%.

7-Methoxy-2-(2-(methoxycarbonyl)benzenesulfonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline186A

Purification (flashmaster: 20 g, gradient elution hex/EtOAc) affordedthe title compound (267 mg, 77%). mp 134-138° C. ¹H NMR (270 MHz; CDCl₃)2.77 (2H, t, J 5.9 Hz, CH₂), 3.48 (2H, t, J 5.9 Hz, CH₂), 3.81 (3H, s,OCH₃), 3.92 (3H, s, OCH₃), 4.33 (2H, s, CH₂), 5.51 (1H, s, OH), 6.51(1H, s, CH), 6.61 (1H, s, CH), 7.46-7.61 (3H, m, 3×CH), 7.84-7.87 (1H,m, CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.24 (CH₂), 43.66 (CH₂), 47.01 (CH₂),53.28 (OCH₃), 56.09 (OCH₃), 108.38 (CH), 114.39 (CH), 123.10 (C), 125.93(C), 128.48 (CH), 129.06 (CH), 130.28 (CH), 132.53 (CH), 133.61 (C),135.71 (C), 144.46 (C), 145.42 (C), 168.57 (C). LC/MS (APCI−) t_(r)=0.81min, m/z 375.91 (M−H)⁻. HPLC t_(r)=1.54 min (>99%).

Sulfamoylations2-(3-Cyano-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline187

50 mg, 58%, colourless solid. mp 183-185° C. ¹H NMR (270 MHz; DMSO-d₆)2.77 (2H, t, J=5.9 Hz, CH₂), 3.35 (2H, brs, under water peak, CH₂), 3.74(3H, s, CH₃), 4.26 (2H, s, CH₂), 6.97 (1H, s, CH), 7.03 (1H,s, CH),7.80-7.86 (3H, m, CH and NH₂), 8.13 (1H, dt, J=7.9, 1.5 Hz, CH), 8.18(1H, dt, J=7.9, 1.5 Hz, CH), 8.29 (1H, t, J=3.1 Hz, CH). ¹³C NMR (100MHz; DMSO-d₆) 27.05 (CH₂), 43.47 (CH₂), 47.02 (CH₂), 55.87 (CH₃), 111.15(CH), 112.82 (C), 117.56 (C), 122.94 (CH), 124.75 (C), 130.35 (C),130.92 (CH), 131.08 (CH), 131.76 (CH), 136.84 (C), 137.52 (CH), 137.55(C), 150.03 (C). LC/MS (ES−) t_(r)=0.94 min, m/z 422.30 (M⁺−H). HPLCt_(r)=3.37 min (>99%). Anal. Calc. for C₁₇H₁₇N₃O₆S₂(H₂O): C 46.25, H4.34, N 9.52. Found: C 46.7, H 4.01, N 9.76%.

7-Methoxy-2-(3-methoxy-benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline188

174 mg, 84%, colourless solid. mp 153-156° C. ¹H NMR (270 MHz; DMSO-d₆)2.77 (2H, t, J=5.5 Hz, CH₂), 3.29 (2H, t, J=5.5 Hz, CH₂), 3.74 (3H, s,OCH₃), 3.83 (3H, s, OCH₃), 4.19 (2H, s, CH₂), 7.00 (1H, s, CH), 7.05(1H, s, CH), 7.26-7.30 (2H, m, 2×CH), 7.39 (1H, d, J=7.7 Hz, CH), 7.57(1H, t, J=7.7 Hz, CH), 7.89 (2H, s, NH₂). ¹³C NMR (67 MHz; DMSO-d₆)27.80 (CH₂), 44.08 (CH₂), 47.67 (CH₂), 56.22 (OCH₃), 56.40 (OCH₃),111.73 (CH), 112.81 (CH), 119.66 (CH), 119.95 (CH), 123.44 (CH), 123.36(C), 131.01 (C), 131.30 (CH), 137.634 (C), 137.99 (C), 150.54 (C),160.10 (C). LC/MS (APCI+) t_(r)=3.62 min, m/z 429.52 (M⁺+H). HPLCt_(r)=3.34 min (>99%). Anal. Calc. for C₁₇H₂₀N₂O₇S₂: C 47.65, H 4.70, N6.54. Found: C 47.0, H 4.65, N 6.48%.

7-Methoxy-6-O-sulfamoyl-2-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline189

176 mg, 69% colourless powder. mp 165-166.5° C. ¹H NMR (270 MHz;DMSO-d₆) 2.76 (2H, t, J=5.9 Hz, CH), 3.39 (2H, t, J=5.9 Hz, CH₂), 3.74(3H, s, OCH₃), 4.28 (2H, s, CH₂), 7.00 (1H, s, CH), 7.02 (1H, s, CH),7.86-7.92 (2H, m, 2×CH), 7.89 (2H, s, NH₂), 8.04 (1H, s, CH), 8.09-8.17(2H, m, 2×CH). ¹³C NMR (100 MHz; DMSO-d₆) 26.94 (CH₂), 43.44 (CH₂),47.00 (CH₂), 55.85 (OCH₃), 111.16 (CH), 112.90 (CH), 123.35 (q, J=267.5Hz, CF₃), 123.74 (q, J=3.8 Hz, CH), 124.69 (C), 130.06 (q, J=3.0 Hz,CH), 130.07 (q, J=32.7 Hz, C—CF₃), 130.32 (C), 131.20 (CH), 131.44 (CH),137.53 (C), 137.72 (C), 150.03 (C). LC/MS (APCI−) t_(r)=1.08 min, m/z465.36 (M⁺−H). HPLC t_(r)=4.08 min (>99%). Anal. Calcd. forC₁₇H₁₇F₃N₂O₆S₂: C 43.77, H 3.67, N 6.01. Found: C 43.7, H 3.72, N 5.90%.

2-(3-Chloro-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline190

119 mg, 65%, colourless powder.mp 154-155° C. ¹H NMR (270 MHz; DMSO-d₆)2.78 (2H, t, J=5.9 Hz, CH), 3.27-3.39 (2H, m, overlapping CH₂), 3.74(3H, s, OCH₃), 4.23 (2H, s, CH₂), 7.00 (1H, s, CH), 7.04 (1H, s, CH),7.64-7.70 (1H, m, CH), 7.78-7.83 (3H, m, 3×CH), 7.88 (2H, s, NH₂). ¹³CNMR (67.5 MHz; DMSO-d₆) 27.70 (CH₂), 44.02 (CH₂), 47.59 (CH₂), 56.40(OCH₃), 111.72 (CH), 123.46 (CH), 125.29 (C), 126.63 (CH), 127.44 (CH),130.90 (C), 132.10 (CH), 133.84 (CH), 134.72 (CH), 138.03 (C), 138.55(C), 150.55 (C). LC/MS (ES−) t_(r)=4.03 min, m/z 431.17 (M−H)⁻. HPLCt_(r)=4.90 min (>96%).

7-Methoxy-6-O-sulfamoyl-2-(toluene-3-sulfonyl)-1,2,3,4-tetrahydroisoquinoline191

26 mg, 47%, colourless powder after recrystallisation from EtOH. mp161-163° C. ¹H NMR (270 MHz; DMSO-d₆) 2.40 (3H, s, CH₃), 2.77 (2H, t,J=5.9 Hz, CH), 3.27 (2H, t, J=5.9 Hz, CH₂), 3.74 (3H, s, OCH₃), 4.16(2H, s, CH₂), 6.99 (1H, s, CH), 7.04 (1H, s, CH), 7.51-7.63 (4H, m,4×CH), 7.88 (2H, s, NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 21.40 (CH₃), 27.79(CH₂), 44.07 (CH₂), 47.67 (CH₂), 56.41 (OCH₃), 111.73 (CH), 123.43 (CH),125.13 (CH), 125.36 (C), 128.11 (CH), 129.86 (CH), 131.01 (C), 134.47(CH), 136.30 (C), 137.99 (C), 139.85 (C), 150.53 (C). LC/MS (ES−)t_(r)=0.99 min, m/z 411.28 (M⁺−H). HPLC t_(r)=3.60 min (>97%).

7-Methoxy-6-O-sulfamoyl-2-(3-trifluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline192

130 mg, 79%, colourless powder. mp 165-167° C. ¹H NMR (270 MHz; DMSO-d₆)2.77 (2H, t, J=5.9 Hz, CH), 3.33-3.41 (2H, m, CH₂), 3.74 (3H, s, OCH₃),4.25 (2H, s, CH₂), 6.99 (1H, s, CH), 7.04 (1H, s, CH), 7.76-7.83 (3H, m,3×CH), 7.87 (1H, t, J=1.8 Hz, CH), 7.89 (2H, brs, NH₂). ¹³C NMR (100MHz; DMSO-d₆) 27.05 (CH₂), 43.47 (CH₂), 47.00 (CH₂), 55.86 (OCH₃),111.15 (CH), 119.94 (CH), 122.93 (CH), 124.72 (C), 125.97 (CH), 126.56(CH), 130.30 (CH), 132.03 (CH), 137.53 (C), 138.35 (C), 148.44 (C),150.04 (C), CF₃ too weak to be seen. ¹⁹F NMR (376 MHz; DMSO-d₆) −55.99(CF ₃). LC/MS (ES−) t_(r)=0.98 min, m/z 481.09 (M⁺−H). HPLC t_(r)=3.89min (>99%). Anal. Calc. for C₁₇H₁₇F₃N₂O₇S₂: C 42.32, H 3.55, N 5.81.Found: C 42.4, H 3.57, N 5.65.

2-(2-Cyano-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline193

90 mg, 90%, colourless foam. mp 194-197° C. ¹H NMR (270 MHz; DMSO-d₆)2.80 (2H, t, J=5.9 Hz, CH₂), 3.53 (2H, t, J=5.9 Hz, CH₂), 3.74 (3H, s,OCH₃), 4.38 (2H, s, CH₂), 6.97 (1H, s, CH), 7.07 (1H, s, CH), 7.86-7.94(3H, m, CH and NH₂), 7.98 (1H, dd, J=7.7, 1.5 Hz, CH), 8.11 (1H, dd,J=7.7, 1.0 Hz, CH), 8.16 (1H, dd, J=7.2, 1.7 Hz, CH). ¹³C NMR (100 MHz;DMSO-d₆) 27.08 (CH₂), 43.10 (CH₂), 46.64 (CH₂), 55.91 (OCH₃), 109.42(C), 111.08 (CH), 116.36 (C), 123.11 (CH), 124.80 (C), 130.13 (CH),130.39 (C), 133.79 (CH), 134.10 (CH), 136.32 (CH), 137.54 (C), 139.42(C), 150.11 (C). LC/MS (ES−) t_(r)=0.98 min, m/z 422.30 (M⁺+H). Anal.Calc. for C₁₇H₁₇N₃O₆S₂: C 48.22, H 4.05, N 9.92. Found: C 48.3, H 4.02,N 9.96%.

7-Methoxy-2-(2-methoxy-benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline194

74 mg, 69%), colourless powder. mp 160-163° C. ¹H NMR (270 MHz; DMSO-d₆)2.62 (2H, t, J=5.9 Hz, CH₂), 3.47 (2H, t, J=5.9 Hz, CH₂), 3.72 (3H, s,OCH₃), 3.74 (3H, s, OCH₃), 4.37 (2H, s, CH₂), 7.0 (1H, s, CH), 7.04 (1H,s, CH), 7.11 (1H, td, J=7.7, 1.0 Hz, CH), 7.18 (1H, d, J=7.9 Hz, CH),7.59-7.66 (1H, m, CH), 7.82 (1H, dd, J=7.9, 1.7 Hz, CH), 7.85 (2H, brs,NH₂). ¹³C NMR (100 MHz; DMSO-d₆) 27.21 (CH₂), 43.04 (CH₂), 46.64 (CH₂),55.83 (OCH₃), 55.90 (OCH₃), 108.98 (CH), 112.94 (CH), 120.21 (CH),122.96 (CH), 125.26 (C), 126.43 (C), 130.68 (CH), 131.54 (C), 134.99(CH), 137.30 (C), 149.99 (C), 156.63 (C). LC/MS (ES+) t_(r)=0.97 min,m/z 451.38 (M⁺+H). HPLC t_(r)=1.27 min (>99%). Anal. Calcd. forC₁₇H₂₀N₂O₇S₂: C 47.65, H 4.70, N 6.54. Found: C 47.7, H 4.73, N 6.54%.

7-Methoxy-2-(4-methoxy-benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline195

147 mg, 72%, colourless solid. mp 83-86° C. ¹H NMR (270 MHz; DMSO-d₆)2.78 (2H, t, J=5.8 Hz, CH₂), 3.23 (2H, t, J=5.8 Hz, CH₂), 3.74 (3H, s,OCH₃), 3.84 (3H, s, OCH₃), 4.12 (2H, s, CH₂), 6.98 (1H, s, CH), 7.05(1H, s, CH), 7.13-7.18 (2H, m, 2×CH), 7.72-7.77 (2H, m, 2×CH), 7.88 (2H,brs, NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 28.87 (CH₂), 44.04 (CH₂), 47.72(CH₂), 56.30 (OCH₃), 56.41 (OCH₃), 111.74 (CH), 115.17 (2×CH), 123.44(CH), 125.38 (C), 127.73 (C), 130.25 (2×CH), 131.04 (C), 138.0 (C),150.55 (C), 163.35 (C). LC/MS (ES+) t_(r)=1.0 min, m/z 451.38 (M⁺+Na).Anal. Calcd. for C₁₇H₂₀N₂O₇S₂: C 47.65, H 4.70, N 6.54. Found: C 47.7, H4.78, N 6.31%. HPLC t_(r)=1.22 min (>99%).

7-Methoxy-2-(2-(methoxycarbonyl)benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline195A

Purification (flashmaster: 10 g, gradient elution hex/EtOAc) affordedthe title compound (138 mg, 71%) as a colourless powder. mp 136-138° C.¹H NMR (270 MHz; DMSO-d₆) 2.76 (2H, t, J=5.6 Hz, CH₂), 3.46 (2H, t,J=5.8 Hz, CH₂), 3.76 (3H, s, OCH₃), 3.86 (3H, s, OCH₃), 4.37 (2H, s,CH₂), 6.97 (2H, s, CH), 7.06 (2H, s, CH), 7.62-7.79 (3H, m, 3×CH), 7.89(2H, brs, NH₂), 7.91-7.95 (1H, m, CH). ¹³C NMR (67.5 MHz; DMSO-d₆) 27.81(CH₂), 43.60 (CH₂), 47.24 (CH₂), 53.52 (OCH₃), 56.46 (OCH₃), 111.52(CH), 123.63 (CH), 125.50 (C), 128.99 (CH), 129.39 (CH), 131.26 (C),131.42 (CH), 133.36 (C), 133.75 (CH), 135.43 (C), 138.01 (C), 150.62(C), 168.37 (C). LC/MS (APCI−) t_(r)=0.82 min, m/z 454.89 (M−H)⁻. HPLCt_(r)=1.46 min (>99%). Anal. Calcd. for C₁₈H₂₀N₂O₈S₂: C 47.36, H 4.42, N6.14. Found C 47.4, H 4.31, N 6.01%.

N-Sulfonyl tetrahydroisoquinolinones6-Benzyloxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one196

To a suspension of sodium hydride (60% dispersion in mineral oil, 46 mg,1.9 mmol) in DMF (5 ml) was added the isoquinlone (300 mg, 1.0 mmol) andthe reaction mixture was heated at 50° C. for 30 min. The reactionmixture was cooled to rt and 3-methoxybenzenesulfonyl chloride (0.15 ml,1.0 mmol) was added dropwise. The reaction mixture was stirred for 3.5 hand turned from yellow to almost colourless after addition of thesulfonyl chloride. A further 0.5 eq (0.07 ml) of the sulfonyl chloridewas added and the reaction mixture stirred for a further 2 h. Thereaction mixture was poured into sat. aq. NaHCO₃ (100 ml) and extractedwith chloroform (3×50 ml). The combined organic layers were washed withwater (4×50 ml) and brine (50 ml), dried (MgSO₄) and concentrated invacuo. Purification by column chromatography eluting with hex:EtOAc; 2:1afforded the title compound (129 mg, 27%) as a colourless foam. mp140-145° C. ¹H NMR (270 MHz; CDCl₃) 2.99 (2H, t, J=6.2 Hz, CH₂), 3.84(3H, s, OCH₃), 3.87 (3H, s, OCH₃), 4.18 (2H, t, J=6.2 Hz; CH₂), 5.18(2H, s, CH₂Ph), 6.64 (1H, s, CH), 7.12 (1H, ddd, J=8.2, 2.7, 1.0 Hz,CH), 7.31-7.44 (6H, m, 6×CH), 7.47 (1H, s, CH), 7.58-7.63 (2H, m, 2×CH).¹³C NMR (100 MHz; CDCl₃) 28.54 (CH₂), 45.07 (CH₂), 55.69 (OCH₃), 56.10(OCH₃), 70.83 (CH₂), 111.02 (CH), 111.11 (CH), 113.16 (CH), 119.94 (CH),120.30 (CH), 120.59 (C), 127.12 (2×CH), 128.20 (CH), 128.71 (2×CH),129.77 (CH), 133.44 (C), 135.88 (C), 140.39 (C), 148.79 (C), 152.59 (C),159.50 (C), 163.27 (C). LC/MS (ES+) t_(r)=1.19 min, m/z 476.50 (M⁺+Na).HPLC t_(r)=4.34 min (>98%).

6-Benzyloxy-7-methoxy-2-(2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one197

314 mg, 65%, colourless solid. mp 202-203° C. ¹H NMR (270 MHz; CDCl₃)2.99 (2H, t, J=6.3 Hz, CH₂), 3.80 (3H, s, OCH₃), 3.88 (3H, s, OCH₃),4.24 (2H, t, J=6.3 Hz, CH₂), 5.19 (2H, s, CH₂Ph), 6.66 (1H, s, CH), 6.96(1H, d, J=8.2 Hz, CH), 7.14 (1H, td, J=7.6, 1.0 Hz, CH), 7.31-7.44 (6H,m, 6×CH), 7.52-7.58 (1H, m, CH), 8.20 (1H, dd, J=7.9, 1.7 Hz, CH). ¹³CNMR (67.5 MHz; CDCl₃) 28.53 (CH₂), 45.34 (CH₂), 56.17 (OCH₃), 56.28(OCH₃), 111.07 (CH), 111.21 (CH), 112.06 (CH), 120.75 (CH), 120.92 (C),127.25 (2×CH), 127.52 (C), 128.30 (CH), 128.84 (2×CH), 132.44 (CH),133.65 (C), 135.44 (CH), 136.09 (C), 148.78 (C), 152.52 (C), 156.60 (C),163.37 (C). LC/MS (ES+) t_(r)=1.08 min, m/z 454.46 (M⁺+H). HPLCt_(r)=1.52 min (>99%). Anal. Calcd. for C₂₄H₂₃NO₆S: C 63.56, H 5.11, N3.09. Found: C 63.5, H 5.11, N 3.20%.

6-Benzyloxy-7-methoxy-2-(4-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one198

152 mg, 32%, colourless oil. ¹H NMR (270 MHz; CDCl₃) 2.97 (2H, t, J=6.3Hz, CH₂), 3.82 (3H, s, OCH₃), 3.87 (3H, s, OCH₃), 4.16 (2H, t, J=6.3 Hz,CH₂), 5.17 (2H, s, CH₂Ph), 6.63 (1H, s, CH), 6.95-6.99 (2H, m, 2×CH),7.28-7.41 (5H, m, 5×CH, phenyl), 7.46 (1H, s, CH), 7.98-8.03 (2H, m,2×CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.66 (CH₂), 44.99 (CH₂), 55.74 (OCH₃),56.20 (OCH₃), 70.95 (CH₂Ph), 111.12 (CH), 111.24 (CH), 114.00 (CH),120.86 (C), 127.23 (CH), 128.29 (CH), 128.82 (CH), 130.78 (C), 130.93(CH), 133.51 (C), 136.04 (C), 148.88 (C), 152.61 (C), 163.45 (C), 163.70(C). LC/MS (ES+) t_(r)=1.16 min, m/z 454.60 (M⁺+H). HPLC t_(r)=1.62 min(>92%).

6-Benzyloxy-2-(3-chloro-benzenesulfonyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one199

259 mg, 54%, yellow foam. mp 155-158° C. ¹H NMR (270 MHz; CDCl₃) 3.00(2H, t, J=6.2 Hz, CH₂), 3.83 (3H, s, OCH₃), 4.18 (2H, t, J=6.2 Hz, CH₂),5.18 (2H, s, CH₂Ph), 6.65 (1H, s, CH), 7.27-7.49 (7H, m, 7×CH), 7.57(1H, ddd, J=7.9, 2.0, 1.2 Hz, CH), 7.96-8.01 (1H, m, CH). ¹³C NMR (67.5MHz; CDCl₃) 28.65 (CH₂), 45.23 (CH₂), 56.23 (OCH₃), 70.96 (CH₂Ph),111.05 (CH), 111.25 (CH), 120.41 (C), 126.94 (CH), 127.24 (CH), 128.34(CH), 128.41 (CH), 128.85 (CH), 130.13 (CH), 133.62 (C), 133.84 (CH),134.98 (C), 135.93 (C), 140.95 (C), 148.97 (C), 152.87 (C), 163.41 (C).LC/MS (ES+) t_(r)=5.66 min, m/z 458.52 (M⁺+H). HPLC t_(r)=1.87 min,>97%.

6-Benzyloxy-7-methoxy-2-(3-carboxymethyl-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one199A

(176 mg, 35%) was obtained as a colourless powder. Recrystallisationfrom DCM and hexane afforded a pure sample. ¹H NMR (270 MHz; CDCl₃) 3.05(2H, t, J 6.2 Hz, CH₂), 3.83 (3H, s, OCH₃), 3.92 (3H, s, OCH₃), 4.19(2H, t, J 6.2 Hz, CH₂), 5.18 (2H, s, CH₂Ph), 6.65 (1H, s, CH), 7.28-7.41(5H, m, 5×CH), 7.46 (1H, s, CH), 7.61-7.71 (3H, m, 3×CH), 8.55 (1H, dd,J 6.4, 2.0 Hz, CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.33 (CH₂), 44.88 (CH₂),53.19 (OCH₃), 56.19 (OCH₃), 70.94 (CH₂), 111.00 (CH), 111.26 (CH),120.74 (C), 127.25 (2×CH), 128.28 (CH), 128.82 (2×CH), 129.07 (CH),130.57 (CH), 132.30 (C), 133.36 (CH), 133.73 (CH), 133.95 (C), 136.07(C), 137.87 (C), 148.79 (C), 152.66 (C), 163.52 (C), 167.24 (C). LC/MS(APCI−) t_(r)=0.95 min, m/z 482.29 (M−H)⁻. HPLC t_(r)=2.0 min (>99%).

Debenzylations6-Hydroxy-7-methoxy-2-(2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one200

145 mg, 57%, colourless powder. mp 222-224° C. ¹H NMR (270 MHz; CDCl₃)3.02 (2H, t, J=6.3 Hz, CH₂), 3.81 (3H, s, OCH₃), 3.88 (3H, s, OCH₃),4.25 (2H, t, J=6.3 Hz, CH₂), 6.07 (1H, s, OH), 6.72 (1H, s, CH), 6.96(1H, d, J=8.4 Hz, CH), 7.12 (1H, t, J=7.7 Hz, CH), 7.42 (1H, s, CH),7.51-7.58 (1H, m, CH), 8.19 (1H, dd, J=7.9, 1.7 Hz, CH). ¹³C NMR (67.5MHz; CDCl₃) 28.35 (CH₂), 45.32 (CH₂), 56.26 (CH₃), 56.27 (OCH₃), 110.66(CH), 112.07 (CH), 112.89 (CH), 120.44 (C), 120.73 (CH), 132.44 (CH),134.59 (C), 135.39 (CH), 145.94 (C), 150.51 (C), 156.62 (C), 163.38 (C).LC/MS (ES−) t_(r)=1.0 min, m/z 362.33 (M−H)⁻. HPLC t_(r)=1.24 min(>99%). Anal. Calcd. for C₁₇H₁₇NO₆S: C 56.19, H 4.72, N 3.85. Found: C55.7, H 4.68, N 3.85%.

6-Hydroxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one201

48 mg, 50%, colourless solid. mp 195-197° C. ¹H NMR (270 MHz; CDCl₃)3.02 (2H, t, J=6.3 Hz, CH₂), 3.84 (3H, s, OCH₃), 3.86 (3H, s, OCH₃),4.19 (2H, t, J=6.3 Hz; CH₂), 6.07 (1H, s, CH), 6.71 (1H, s, CH), 7.11(1H, ddd, J=8.4, 2.6, 1.0 Hz, CH), 7.41 (1H, t, J=8.1 Hz, CH), 7.45 (1H,s, CH), 7.57-7.63 (2H, m, 2×CH). ¹³C NMR (100 MHz; CDCl₃) 28.42 (CH₂),45.10 (CH₂), 55.70 (OCH₃), 56.21 (OCH₃), 110.63 (CH), 112.82 (CH),113.13 (CH), 119.96 (CH), 120.15 (C), 120.34 (CH), 129.78 (CH), 134.43(C), 140.51 (C), 145.93 (C), 150.60 (C), 159.54 (C), 163.31 (C). LC/MS(ES−) t_(r)=1.08 min, m/z 362.42 (M−H)⁻. HPLC t_(r)=1.28 min (>99%).Anal. Calcd. for C₁₇H₁₇NO₆S: C 56.19, H 4.72, N 3.85. Found: C 56.0, H4.80, N 3.67%.

6-Hydroxy-7-methoxy-2-(4-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one202

74 mg, 62%, colourless powder. mp 202-204° C. ¹H NMR (270 MHz; CDCl₃)3.0 (2H, t, J=6.3 Hz, CH₂), 3.84 (3H, s, OCH₃), 3.85 (3H, s, OCH₃), 4.17(2H, t, J=6.2 Hz, CH₂), 6.08 (1H, s, OH), 6.70 (1H, s, CH), 6.95-6.99(2H, m, 2×CH), 7.45 (1H, s, CH), 7.99-8.03 (2H, m, 2×CH). ¹³C NMR (100MHz; CDCl₃) 23.37 (CH₂), 44.89 (CH₂), 55.63 (OCH₃), 56.16 (OCH₃), 110.51(CH), 112.77 (CH), 113.89 (2×CH), 120.21 (C), 130.68 (C), 130.80 (2×CH),134.37 (C), 145.87 (C), 150.45 (C), 163.39 (C), 163.57. LC/MS (ES−)t_(r)=1.25 min, m/z 362.33 (M−H)⁻. HPLC t_(r)=1.25 min (>99%).

2-(3-Chloro-benzenesulfonyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one203

158 mg, 82%, colourless solid. mp 178-181° C. ¹H NMR (270 MHz; CDCl₃)3.03 (2H, t, J=6.2 Hz, CH₂), 3.85 (3H, s, OCH₃), 4.19 (2H, t, J=6.3 Hz;CH₂), 6.11 (1H, s, OH), 6.72 (2H, s, CH₂), 7.44 (1H, s, CH), 7.44-7.50(1H, m, CH), 7.54-7.59 (1H, m, CH), 7.96-8.0 (1H, m, CH, 8.02 (1H, t,J=1.5 Hz, CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.46 (CH₂), 45.25 (CH₂), 56.31(OCH₃), 110.64 (CH), 113.02 (CH), 119.89 (C), 126.87 (CH), 128.45 (CH),130.11 (CH), 133.80 (CH), 134.58 (C), 134.95 (C), 140.99 (C), 146.11(C), 150.93 (C), 163.44 (C). LC/MS (ES−) t_(r)=1.12 min, m/z 366.46(M−H)⁻. HPLC t_(r)=1.38 min (>99%). Anal. Calcd. for C₁₆H₁₄ClNO₅S: C52.25, H 3.84, N 3.81. Found: C 52.0, H 4.02, N 3.66%.

6-Hydroxy-7-methoxy-2-(3-carboxymethyl-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one203A

Purification (flashmaster: 20 g, gradient elution hex/EtOAc) affordedthe title compound (99 mg, 76%) as a colourless solid. mp 236-239° C. ¹HNMR (270 MHz; CDCl₃) 3.08 (2H, t, J=6.2 Hz, CH₂), 3.83 (3H, s, OCH₃),3.93 (3H, s, OCH₃), 4.19 (2H, t, J=6.2 Hz, CH₂), 6.08 (1H, s, OH), 6.71(1H, s, CH), 7.44 (1H, s, CH), 7.60-7.70 (3H, m, 3×CH), 8.54 (1H, dd,J=6.2, 1.7 Hz, CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.15 (CH₂), 44.88 (CH₂),53.21 (OCH₃), 56.26 (OCH₃), 110.52 (CH), 112.92 (CH), 120.23 (C), 129.06(CH), 130.53 (CH), 132.43 (C), 133.34 (CH), 133.70 (CH), 134.91 (C),137.91 (C), 145.90 (C), 150.62 (C), 163.55 (C), 167.25 (C). LC/MS(APCI−) t_(r)=0.86 min, m/z 390.08 (M−H)⁻. HPLC t_(r)=1.56 min (>99%).Anal. Calcd. for C₁₈H₁₇NO₇S: C 55.24, H 4.38, N 3.58. Found: C 55.3, H3.42, N 4.42%.

Sulfamoylations7-Methoxy-2-(2-methoxy-benzenesulfonyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one204

115 mg, 75%, white powder. mp 195-197° C. ¹H NMR (270 MHz; DMSO-d₆) 3.09(2H, t, J=6.2 Hz, CH₂), 3.78 (3H, s, OCH₃), 3.89 (3H, s, OCH₃), 4.18(2H, t, J=6.2 Hz, CH₂), 7.18 (1H, t, J=7.7 Hz, CH), 7.24 (1H, d, J=8.4Hz, CH), 7.37 (1H, s, CH), 7.44 (1H, s, CH), 7.68 (1H, td, J=8.4, 1.6Hz, CH), 7.79 (1H, dd, J=7.8, 1.6 Hz, CH), 8.14 (2H, brs, NH₂). ¹³C NMR(67.5 MHz; DMSO-d₆) 27.71 (CH₂), 45.60 (CH₂), 56.60 (OCH₃), 57.04(OCH₃), 112.62 (CH), 113.61 (CH), 120.81 (CH), 122.47 (CH), 126.45 (C),127.27 (C), 131.84 (CH), 133.50 (C), 136.34 (CH), 143.36 (C), 151.28(C), 156.96 (C), 162.42 (C). LC/MS (ES−) t_(r)=0.96 min, m/z 441.17(M−H)⁻. HPLC t_(r)=1.24 min (>99%). Anal. Calcd. for C₁₇H₁₈N₂O₈S₂: C46.15, H 4.10, N 6.33. Found: C 45.8, H 4.04, N 6.20%

7-Methoxy-2-(3-methoxy-benzenesulfonyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one205

18 mg, 49%, colourless powder. mp 164-166° C. ¹H NMR (270 MHz; DMSO-d₆)3.12 (2H, t, J=6.1 Hz, CH₂), 3.78 (3H, s, OCH₃), 3.84 (3H, s, OCH₃),4.21 (2H, t, J=6.1 Hz, CH₂), 7.30 (1H, dt, J=7.6, 2.1 Hz, CH), 7.36 (1H,s, CH), 7.47 (2H, brs, 2×CH), 7.52-7.61 (2H, m, 2×CH), 8.15 (2H, brs,NH₂). LC/MS (ES−) t_(r)=1.0 min, m/z 441.38 (M−H)⁻. HPLC t_(r)=1.27 min(>99%).

7-Methoxy-2-(4-methoxy-benzenesulfonyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one206

30 mg, 56%, colourless solid. mp 177-180° C. ¹H NMR (400 MHz; DMSO-d₆)3.09 (2H, t, J=6.0 Hz, CH₂), 3.79 (3H, s, OCH₃), 3.86 (3H, s, OCH₃),4.17 (2H, t, J=6.2 Hz, CH₂), 7.12-7.16 (2H, m, 2×CH), 7.34 (1H, s, CH),7.46 (1H, s, CH), 7.94-7.97 (2H, m, 2×CH), 8.13 (2H, brs, NH₂). ¹³C NMR(100 MHz; DMSO-d₆) 27.21 (CH₂), 44.75 (CH₂), 55.84 (OCH₃), 56.05 (OCH₃),111.99 (CH), 114.22 (2×CH), 121.85 (CH), 125.79 (C), 130.10 (C), 130.55(2×CH), 132.94 (C), 142.85 (C), 150.69 (C), 162.06 (C), 163.36 (C).LC/MS (ES−) t_(r)=0.94 min, m/z 441.31 (M−H)⁻. HPLC t_(r)=1.28 min(>99%). Anal. Calcd. for C₁₇H₁₈N₂O₈S₂: C 46.15, H 4.10, N 6.33, Found :C 45.8, H 4.08, N 6.21%.

2-(3-Chloro-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one207

132 mg, 90%, colourless solid. mp 170-173° C. ¹H NMR (270 MHz; DMSO-d₆)3.14 (2H, t, J=6.2 Hz, CH₂), 3.79 (3H, s, OCH₃), 4.24 (2H, t, J=6.2 Hz;CH₂), 7.37 (1H, s, CH), 7.48 (1H, s, CH), 7.68 (1H, t, J=8.0 Hz, CH),7.82-7.85 (1H, m, CH), 8.0 (1H, d, J=8.2 Hz, CH), 8.06 (1H, t, J=1.8 Hz,CH), 8.17 (2H, s, NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 27.73 (CH₂), 45.51(CH₂), 56.65 (OCH₃), 112.62 (CH), 122.46 (CH), 126.02 (C), 127.33 (CH),128.22 (CH), 131.77 (CH), 133.68 (C), 134.14 (C), 134.58 (CH), 141.17(C), 143.59 (C), 151.28 (C), 162.86 (C). LC/MS (ES−) t_(r)=1.02 min, m/z445.30 (M−H)⁻. HPLC t_(r)=1.28 min (>97%). Anal. Calcd. forC₁₆H₁₅ClN₂O₇S₂: C 43.0, H 3.38, N 6.27. Found: C 42.9, H 3.43, N 6.20%.

6-O-Sulfamoyl-7-methoxy-2-(3-carboxymethyl-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one207A

Purification (flashmaster: 10 g, gradient elution hex/EtOAc) affordedthe title compound (49 mg, 60%) as a colourless powder. mp 181-186° C.¹H NMR (270 MHz; DMSO-d₆) 3.14 (2H, t, J=5.8 Hz, CH₂), 3.80 (3H, s,OCH₃), 3.88 (3H, s, OCH₃), 4.13 (2H, t, J=5.8 Hz, CH₂), 7.37 (1H, s,CH), 7.49 (1H, s, CH), 7.72-7.87 (3H, m, 3×CH), 8.16 (2H, brs, NH₂),8.32-8.35 (1H, m, CH). ¹³C NMR (67.5 MHz; DMSO-d₆) 27.49 (CH₂), 45.04(CH₂), 53.78 (CH₃), 56.63 (CH₃), 112.62 (CH), 122.46 (CH), 126.17 (C),129.67 (CH), 131.33 (CH), 132.66 (C), 132.97 (CH), 133.52 (C), 134.77(CH), 136.98 (C), 143.49 (C), 151.30 (C), 162.62 (C), 167.47 (C). LC/MS(APCI−) t_(r)=0.86 min, m/z 390.02 (M−SO₂NH₂)⁻. HPLC t_(r)=1.48 min(>99%). Anal. Calcd. for C₁₈H₁₈N₂O₉S₂: C 45.95, H 3.86, N 5.95. Found C46.0, H 3.93, N 5.87%.

Experimental for Substituted Tetrahydroisoquinolines2-(Benzyloxy)-1-methoxy-4-((E)-2-nitroprop-1-enyl)benzene 208

3-Benzyloxy-4-methoxybenzaldehyde (8.0 g, 33.05 mmol), ammonium acetate(2.55 g, 33.05 mmol) and nitroethane (120 ml) were stirred under refluxfor 22 h. The reaction mixture was cooled to rt and nitroethane wasremoved in vacuo. The solid residue was dissolved in ethyl acetate (200ml), washed with water (40 ml) and brine (2×40 ml), dried (MgSO₄) andconcentrated in vacuo. Recrystallisation from ethanol afforded the titlecompound (6.19 g, 63%) as yellow crystals. mp=102-104° C. ¹H NMR (270MHz; CDCl₃) 2.27 (3H, s, CH₃), 3.94 (3H, s, OCH₃), 5.19 (2H, s, CH₂Ph),6.91 (1H, d, J=2.0 Hz, CH), 6.94 (1H, d, J=8.4 Hz, CH), 7.05 (1H, dd,J=8.4, 2.0 Hz, CH), 7.30-7.43 (4H, m, 4×CH), 7.97 (1H, s, CH). ¹³C NMR(67.5 MHz; CDCl₃) 14.03 (CH₃), 56.15 (OCH₃), 71.25 (CH₂Ph), 111.69 (CH),115.77 (CH), 124.93 (C), 124.94 (CH), 127.16 (CH), 128.19 (CH), 128.83(CH), 133.84 (CH), 136.65 (C), 145.92 (C), 148.00 (C), 151.51 (C). LC/MS(APCI−) t_(r)=1.07 min, m/z 297.93 (M−H)⁻.

2-(Benzyloxy)-1-methoxy-4-(2-nitropropyl)benzene 209

To a suspension of sodium borohydride (1.52 g, 40 mmol) in ethanol (20ml) at 0° C. was added a solution of 208 (6 g, 20 mmol) in THF (40 ml).The addition was over 20 min, the reaction mixture was stirred for 1 hat 0° C. and at rt for 30 min. 2M HCl (20 ml) was added (care—vigorousreaction!) and ethyl acetate (100 ml). The layers were separated and theaqueous layer was extracted with ethyl acetate (2×60 ml). The combinedorganic layers were washed with water (60 ml) and brine (60 ml), dried(MgSO₄) and concentrated in vacuo to afford the crude material as anorange oil. Purification by flash column chromatography eluting withhex:EtOAc; 4:1 afforded the title compound (3.35 g, 55%) as a pale greensolid. ¹H NMR (270 MHz; CDCl₃) 1.44 (3H, d, J=6.7 Hz, CH₃), 2.87 (1H,dd, J=14.1, 6.9 Hz, one of CH₂), 3.19 (1H, dd, J 14.1, 7.4 Hz, one ofCH₂), 3.85 (3H, s, OCH₃), 4.65 (1H, sext, J=6.9 Hz, CH), 5.12 (2H, s,CH₂Ph), 6.65-6.71 (2H, m, 2×CH), 6.81 (1H, d, J=8.2 Hz, CH), 7.25-7.43(5H, m, 5×CH). ¹³C NMR (67.5 MHz; CDCl₃) 18.71 (CH₃), 40.80 (CH₂), 56.08(OCH₃), 71.17 (CH₂), 84.64 (CH), 112.0 (CH), 115.15 (CH), 121.93 (CH),127.47 (CH), 127.87 (C), 128.0 (CH), 128.67 (CH), 136.99 (C), 148.14(C), 149.13 (C), LC/MS (APCI−) t_(r)=1.1 min, m/z 300.01 (M−H)⁻.

1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-amine 210

Raney nickel (50%, slurry in water, 2.0 g) was washed with MeOH (3×). Tothis was added MeOH (70 ml) and 209 (3.05 g, 10.1 mmol). The mixture wascooled (ice-bath) and hydrazine hydrate (2.53 g, 50.5 mmol) was addeddropwise. The mixture was heated to 40° C. for 1 h, then further Raneynickel (50% slurry in water, 1.0 g) was added as a suspension in MeOH(10 ml). The reaction mixture was heated at 40° C. for a further 18 h.The resulting solution was cooled to rt and filtered through celite,washing through with MeOH (200 ml). The filtrate was concentrated invacuo and purification (flashmaster: 50 g, EtOAc/MeOH) afforded thetitle compound (2.074 g, 76%) as a pale yellow oil. ¹H NMR (270 MHz;CDCl₃) 1.04 (3H, d, J=6.4 Hz, CH₃), 2.36 (1H, dd, J=13.3, 8.2 Hz, CHH),2.58 (1H, dd, J=13.3, 5.2 Hz, CHH), 2.98-3.1 (1H, m, CH), 3.86 (3H, s,OCH₃), 5.13 (2H, s, CH₂), 6.67-6.83 (3H, m, 3×CH), 7.25-7.43 (5H, m,5×CH, phenyl). LC/MS (ES+) t_(r)=1.82 min, m/z 272.19 (M⁺+H).

N-(1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-yl)acetamide 211

To a solution of 210 (2.07 g, 7.6 mmol) was added triethyl amine (1.6ml, 11.4 mmol). The solution was cooled to 0° C. and acetic anhydridewas added slowly dropwise. The reaction mixture was stirred at 0° C. for1 h and then at rt for 23 h. Water (30 ml) and DCM (30 ml) were added,the layers separated and the aqueous layer extracted with DCM (3×30 ml).The combined organic phases were washed with brine (30 ml), dried(MgSO₄) and concentrated in vacuo to afford the title compound (2.268 g,95%) as a white powder. mp=139.142° C. ¹H NMR (270 MHz; CDCl₃) 0.99 (3H,d, J=6.7 Hz, CH₃CH), 1.91 (3H, s, CH₃CO), 2.57 (1H, dd, J=13.6, 7.2 Hz,CH), 2.70 (1H, dd, J=13.6, 5.7 Hz, CH), 3.85 (3H, s, OCH₃), 4.1-4.22(1H, m, CH), 5.12 (2H, s, CH₂Ph), 5.17-5.23 (1H, m, NH), 6.68-6.71 (2H,m, 2×CH), 6.79-6.82 (1H, m, CH), 7.24-7.44 (5H, m, 5×CH, phenyl). ¹³CNMR (67.5 MHz; CDCl₃) 19.86 (CH₃), 23.62 (CH₃), 41.84 (CH₂), 46.07 (CH),56.12 (OCH₃), 71.07 (CH₂), 111.83 (CH), 115.62 (CH), 122.21 (CH), 127.40(CH), 127.90 (CH), 128.62 (CH), 130.36 (C), 137.23 (C), 147.91 (C),148.45 (C), 169.31 (C). LC/MS (APCI−) t_(r)=0.89 min, m/z 312.29 (10%,M−H⁻), 21 1.95 (82), 120.85 (100).

1-(6-(Benzyloxy)-3,4-dihydro-7-methoxy-3-methylisoquinolin-2(1H)-yl)ethanone212

Paraformaldehyde (6.32 g) was added portionwise to a solution of 211(2.21 g, 7.04 mmol) in toluene (55 ml) with pTSA (60 mg). The reactionmixture was heated under reflux for 2 h. Further paraformaldehyde (632mg) was added and heating under reflux was continued overnight.Additional pTSA (60 mg) and paraformaldehyde (1.9 g) was added to thereaction mixture portionwise over 2 h. The solution was cooled to rt,water (50 ml) and ethyl acetate (60 ml) were added. The layers wereseparated and the organic layer was washed with water (2×50 ml) andbrine (50 ml), dried (MgSO₄) and concentrated in vacuo to afford thetitle compound (2.15 g, 94%) as a colourless oil. ¹H NMR indicated amixture of conformers, signals for both conformers are listed 1.04, 1.12(3H, d, J=6.7 Hz, CH ₃CH), 2.14, 2.17 (3H, s, CH₃CO), 2.38-2.51 (1H, m,CHH for both conformers), 2.89-3.06 (1H, m, CHH for both conformers),3.84, 3.85 (3H, s, OCH₃), 4.06-4.6 (2H, m, CH₂ for both conformers),5.01-5.02 (3H, m, CHCH₃ and CH ₂Ph for both conformers), 6.6-6.64 (2H,m, 2×CH for both conformers), 7.28-7.44 (5H, m, 5×CH, phenyl for bothconformers). LC/MS (ES+) t_(r)=1.02 min, m/z 348.19 (M⁺+Na).

6-(Benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinoline 213

A solution of 212 (2.1 g, 6.5 mmol) in EtOH (60 ml) with 10% NaOH (15ml) was heated under reflux for 20 h. A further 15 ml of 10% NaOH wasadded and heating continued for another 24 h. The reaction mixture wascooled to rt and concentrated to remove the EtOH. Chloroform (30 ml) wasadded, the layers separated and the aqueous layers extracted withchloroform (3×). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo to afford an orange oil. Purification by flashcolumn chromatography eluting with EtOAc to 20% MeOH/80% EtOAc/0.5% TEAafforded the title compound (858 mg, 47%) as an orange powder. ¹H NMR(270 MHz; CDCl₃) 1.20 (3H, d, J=6.4 Hz, CH ₃CH), 1.46 (1H, brs, NH),2.35 (1H, dd, J=15.8, 10.6 Hz, CHH), 2.61 (1H, dd, J=15.8, 3.7 Hz, CHH),2.88-3.0 (1H, m, CH₃CH), 3.83 (3H, s, OCH₃), 3.93 (1H, d, J=15.6 Hz, oneof ArCH₂N), 4.04 (1H, d, J=15.6 Hz, one of ArCH₂N), 5.09 (2H, s, CH₂Ph),6.54 (1H, s, CH), 6.57 (1H, s, CH), 7.25-7.43 (5H, m, 5×CH, phenyl). ¹³CNMR (67.5 MHz; CDCl₃) 22.60 (CH₃), 36.76 (CH₂), 48.43 (CH₂), 49.37 (CH),56.16 (OCH₃), 71.23 (CH₂), 109.51 (CH), 114.75 (CH), 126.82 (C), 127.37(CH), 127.82 (CH), 128.09 (C), 128.59 (CH), 137.41 (C), 146.62 (C),148.0 (C). LC/MS (ES+) t_(r)=1.21 min, m/z 284.13 (M⁺+H). HPLCt_(r)=2.49 min (>99%).

2-(3-Methoxybenzyl)-6-(benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinoline214

General Method:

A solution of 213 (300 mg, 1.1 mmol), TEA (0.3 ml, 2.1 mmol) and3-methoxybenzyl chloride (0.18 ml, 1.3 mmol) in EtOH (3 ml) was heatedin the microwave at 130° C. for 1.5 h. The reaction mixture wasconcentrated in vacuo and the crude residue was dissolved in EtOAc (30ml) and washed with brine (30 ml). The organic layer was dried (MgSO₄)and concentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to100% EtOAc over 25 min) afforded the title compound (357 mg, 84%) as acolourless oil. ¹H NMR (270 MHz; CDCl₃) 1.12 (3H, d, J=6.4 Hz, CH ₃CH),2.47 (1H, dd, J=16.1, 5.7 Hz, CHH), 2.86 (1H, dd, J=16.1, 4.9 Hz, CHH),3.0-3.11 (1H, m, CH₃CH), 3.55 (2H, t, J=13.4 Hz, CH₂), 3.76-3.81 (2H, m,CH₂), 3.80 (6H, s, 2×OCH₃), 5.10 (2H, s, CH₂Ph), 6.47 (1H, s, CH), 6.60(1H, s, CH), 6.79 (1H, ddd, J=8.2, 2.5, 1.0 Hz, CH), 6.94-6.97 (2H, m,2×CH), 7.15-7.45 (6H, m, 5×CH, phenyl and CH). ¹³C (67.5 MHz; CDCl₃)15.31 (CH₃), 35.03 (CH₂), 51.51 (CH₂), 52.27 (CH), 55.32 (CH₃), 56.11(CH₃), 57.24 (CH₂), 71.21 (CH₂), 109.95 (CH), 112.48 (CH), 114.36 (CH),114.56 (CH), 121.32 (CH),125.83 (C), 126.95 (C), 127.37 (CH), 127.82(CH), 128.59 (CH), 129.30 (CH), 137.47 (C), 141.35 (C), 146.73 (C),147.91 (C), 159.77 (C). LC/MS (ES+) t_(r)=1.52 min, m/z 404.25 (M⁺+H).

2-(3,5-Dimethoxybenzyl)-6-(benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinoline215

Method as for 214 afforded the title compound (222 mg, 46%) as acolourless oil. ¹H NMR (270 MHz; CDCl₃) 1.10 (3H, d, J=6.4 Hz, CH ₃CH),2.45 (1H, dd, J=15.9, 5.8 Hz, CHH), 2.86 (1H, dd, J=15.9, 4.7 Hz, CHH),3.02-3.11 (1H, m, CH₃CH), 3.45-3.71 (4H, m, 2×CH₂), 3.77 (6H, s, 2×CH₃),3.79 (3H, s, OCH₃), 5.09 (2H, s, CH₂Ph), 6.35 (1H, t, J=2.2 Hz, CH),6.48 (1H, s, CH), 6.54 (1H, d, J=2.2 Hz, CH), 6.60 (1H, s, CH),7.28-7.44 (5H, m, 5×CH, phenyl). ¹³C (67.5 MHz; CDCl₃) 15.22 (CH₃),34.94 (CH₂), 51.48 (CH₂), 52.15 (CH), 55.43 (CH₃), 56.11 (CH₃), 57.40(CH₂), 71.21 (CH₂), 99.03 (CH), 106.72 (CH), 109.96 (CH), 114.53 (CH),125.79 (C), 126.93 (C), 127.37 (CH), 127.82 (CH), 128.58 (CH), 137.46(C), 142.16 (C), 146.73 (C), 147.91 (C), 160.81 (C). LC/MS (ES+)t_(r)=1.43 min, m/z 434.36 (M⁺+H). HRMS (ES+) calcd. for C₂₇H₃₂NO₄434.2326, found 434.2330. HPLC t_(r)=3.74 min (>94%).

2-(3,4,5-Trimethoxybenzyl)-6-(benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinoline216

Method as for 214 afforded the title compound as a colourless oil (190mg, 34%). ¹H NMR (270 MHz; CDCl₃) 1.11 (3H, d, J=6.4 Hz, CH₃CH), 2.46(1H, dd, J=16.1, 5.7 Hz, CHH), 2.87 (1H, dd, J 16.1, 4.8 Hz, CHH),3.04-3.11 (1H, m, CH), 3.46-3.75 (4H, m, 2×CH₂), 3.80 (3H, s, OCH₃),3.84 (3H, s, OCH₃), 3.84 (6H, s, 2×OCH₃), 5.10 (2H, s, CH₂Ph), 6.50 (1H,s, CH), 6.60 (2H, s, 2×CH), 6.61 (1H, s, CH), 7.26-7.44 (5H, m, 5×CH).¹³C NMR (67.5 MHz; CDCl₃) 15.09 (CH₃), 34.76 (CH₂), 51.37 (CH₂), 52.02(CH), 56.13 (OCH₃), 56.20 (OCH₃), 57.37 (CH₂), 60.98 (OCH₃), 71.16(CH₂), 105.44 (CH), 109.91 (CH), 114.44 (CH), 125.75 (C), 126.81 (C),127.37 (CH), 127.84 (CH), 128.61 (CH), 135.37 (C), 136.71 (C), 146.65(C), 146.75 (C), 147.90 (C), 153.20 (C). LC/MS (ES+) t_(r)=0.64 min, m/z464.22 (M⁺+H). HRMS (ES+) calcd. for C₂₈H₃₄NO₅ (M⁺+H) 464.2431, found464.2436. HPLC t_(r)=3.46 min (>94%).

2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-ol217

A solution of 214 (330 mg, 0.82 mmol) in THF (6 mL) and EtOH (6 mL) wastreated with 10% Pd/C (33 mg) and stirred under an atmosphere ofhydrogen. The reaction was monitored by TLC. Upon completion, theresultant suspension was filtered through celite, washed with ethylacetate and then evaporated under reduced pressure. Purification(personal flashmaster: 20 g, hex:EtOAc; 2:1) afforded the title compound(118 mg, 46%) as a pale yellow solid. mp=100-105° C. ¹H NMR (270 MHz;CDCl₃) 1.12 (3H, d, J=6.7 Hz, CH ₃CH), 2.49 (1H, dd, J=16.1, 5.8 Hz,CHH), 2.89 (1H, dd, J=16.1, 4.8 Hz, CHH), 3.01-3.12 (1H, m, CHCH₃),3.48-3.74 (4H, m, 2×CH₂), 3.78 (3H, s, OCH₃), 3.79 (3H, s, OCH₃), 5.42(1H, s, OH), 6.42 (1H, s, CH), 6.63 (1H, s, CH), 6.77-6.81 (1H, m, CH),6.93-6.96 (2H, m, 2×CH), 7.21 (1H, d, J=8.2 Hz, CH). ¹³C NMR (67.5 MHz;CDCl₃) 15.39 (CH₃), 34.68 (CH₂), 51.43 (CH₂), 52.30 (CH), 55.31 (OCH₃),55.99 (OCH₃), 57.07 (CH₂), 108.73 (CH), 112.54 (CH), 114.35 (CH), 114.54(CH), 121.36 (CH), 125.48 (C), 126.56 (C), 129.29 (CH), 141.20 (C),144.04 (C), 144.92 (C), 159.75 (C). LC/MS (ES+) t_(r)=2.43 min, m/z314.18 (M⁺+H). HRMS (ES+) calcd. for C₁₉H₂₄NO₃ 314.1751, found 314.1748.

2-(3,5-Dimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-ol218

Method as for 217 to afford the title compound (81 mg, 69%) as a paleyellow powder. mp=155-158° C. ¹H NMR (270 MHz; CDCl₃) 1.12 (3H, d, J=6.4Hz, CH₃CH), 2.48 (1H, dd, J=16.1, 5.8 Hz, CHH), 2.88 (1H, dd, J=16.1,4.7 Hz, CHH), 3.0-3.12 (1H, m, CH₃CH), 3.47-3.78 (4H, m, 2×CH₂), 3.78(6H, m, 2×CH₃), 3.79 (3H, s, OCH₃), 5.52 (1H, brs, OH), 6.35 (1H, t,J=2.3 Hz, CH), 6.43 (1H, s, CH), 6.55 (2H, d, J=2.3 Hz, CH), 6.62 (1H,s, CH). LC/MS (ES+) t_(r)=1.01 min, m/z 344.16 (M⁺+H). HRMS (ES+) calcd.for C₂₀H₂₆NO₄ 344.1856, found 344.1857. HPLC t_(r)=2.33 min (>90%).

2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-ol219

Method as for 217 to afford the title compound (80 mg, 66%) as a yellowsolid. mp=127-132° C. ¹H NMR (270 MHz; CDCl₃) 1.13 (3H, d, J=6.2 Hz, CH₃CH), 2.49 (1H, dd, J=16.0, 5.8 Hz, CHH), 2.90 (1H, dd, J=16.0, 4.9 Hz,CHH), 3.08-3.11 (1H, m, CHCH₃), 3.47-3.80 (4H, m, 2×CH₂), 3.80 (3H, s,OCH₃), 3.83 (3H, s, OCH₃), 3.84 (6H, s, 2×OCH₃), 5.52 (1H, brs, OH),6.45 (1H, s, CH), 6.61 (2H, s, 2×CH), 6.64 (1H, s, CH). ¹³C NMR (67.5MHz; CDCl₃) 15.19 (CH₃), 34.58 (CH₂), 51.39 (CH₂), 52.12 (CH), 56.03(OCH₃), 56.21 (OCH₃), 57.31 (CH₂), 60.94 (OCH₃), 105.56 (CH), 108.76(CH), 114.58 (CH), 125.59 (C), 126.61 (C), 135.39 (C), 144.08 (C),144.96 (C), 155.23 (C). LC/MS (ES−) t_(r)=0.94 min, m/z 372.32 (M⁺−H).HRMS (ES+) calcd. for C₂₁H₂₈NO₅ 374.1962, found 374.1964. HPLCt_(r)=2.23 min (>81%).

2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-O-sulfamate220

A solution of sulfamoyl chloride in toluene (0.6M, 2.33 ml, 1.4 mmol)was concentrated in vacuo and cooled in an ice bath until the sulfamoylchloride solidified. DMA (1 ml) was added and the resulting solution wasadded directly to 217 (88 mg, 0.28 mmol) at 0° C. The reaction wasstirred at rt for 16 h. Water (10 ml) was added and solid sodiumhydrogen carbonate to neutralise and the aqueous layer was extractedwith ethyl acetate (3×20 ml). The combined organic layers were washedwith water (4×20 ml), dried (MgSO₄) and concentrated in vacuo.Purification (flashmaster: 20 g, gradient elution 100% hex-100% EtOAcover 20 min) afforded the title compound (56 mg, 51%) as a pale yellowsolid. mp=154-156° C. ¹H NMR (270 MHz; DMSO-d₆) 1.06 (3H, d, J=6.5 Hz,CH₃CH), 2.44-2.51 (1H, m, CHH), 2.89 (1H, dd, J=16.0, 4.6 Hz, CH ₃CH),3.01-3.07 (1H, m, CHCH₃), 3.46-3.60 (4H, m, 2×CH₂), 3.70 (3H, s, OCH₃),3.73 (3H, s, OCH₃), 6.79 (1H, s, CH), 6.82 (1H, dd, J=7.2, 2.02 Hz, CH),6.89-6.94 (2H, m, 2×CH), 7.02 (1H, s, CH), 7.24 (1H, t, J=8.0 Hz, CH),7.85 (2H, brs, NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 14.99 (CH₃), 39.752(CH₂), 52.05 (CH), 55.48 (OCH₃), 56.29 (OCH₃), 57.34 (CH₂), 111.47 (CH),112.74 (CH), 114.44 (CH), 121.21 (CH), 123.64 (CH), 125.88 (C), 129.84(CH), 133.61 (C), 141.66 (C), 150.13 (C), 159.86 (C). LC/MS (ES+)t_(r)=0.63 min, m/z 393.10 (M⁺+H). HPLC t_(r)=1.91 min (>98%).

2-(3,5-dimethoxy-benzyl)-7-methoxy-3-methyl-1,2,3,4-tetrahydro-isoquinolin-6-O-sulfamate221

Sulfamoylation following the method of 220 afforded the title compound(80 mg, 64%) as a pale yellow solid. mp=146-149° C. ¹H NMR (270 MHz;DMSO-d₆) 1.05 (3H, d, J=6.2 Hz, CH₃CH), 2.43-2.51 (1H, m, CHH), 2.88(1H, dd, J=16.0, 4.7 Hz, CH ₃CH), 3.0-3.07 (1H, m, CHCH₃), 3.66-3.99(4H, m, 2×CH₂), 3.70 (3H, s, OCH₃), 3.71 (6H, s, 2×OCH₃), 6.37 (1H, t,J=2.2 Hz, CH), 6.51 (1H, d, J=2.2 Hz, CH), 6.80 (1H, s, CH), 7.02 (1H,s, CH), 7.85 (2H, brs, NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 14.96 (CH₃),39.42 (CH₂), 51.20 (CH₂), 52.0 (CH), 55.63 (OCH₃), 56.3 (OCH₃), 57.49(CH₂), 99.10 (CH), 106.73 (CH), 111.50 (CH), 123.64 (CH), 125.88 (C),133.63 (C), 137.60 (C), 142.51 (C), 150.14 (C), 160.97 (C). LC/MS (ES+)t_(r)=0.62 min, m/z 423.09 (M⁺+H). HRMS (ES+) calcd. for C₂₀H₂₇N₂O₆S423.1584, found 423.1580. HPLC t_(r)=1.85 min (>95%).

2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-O-sulfamate222

Sulfamoylation following the method of 220 afforded the title compound(55 mg, 70%) as a yellow powder. mp=137-143° C. ¹H NMR (270 MHz;DMSO-d₆) 1.06 (3H, d, J=6.4 Hz, CH ₃CH), 2.44-2.51 (1H, m, CHH), 2.90(1H, dd, J=16.5, 5.1 Hz, CHH), 3.03-3.09 (1H, m, CHCH₃), 3.49-3.66 (4H,m, 2×CH₂), 3.64 (3H, s, OCH₃), 3.71 (3H, s, OCH₃), 3.75 (6H, s, 2×OCH₃),6.65 (2H, s, 2×CH), 6.82 (1H, s, CH), 7.03 (1H, s, CH), 7.82 (2H, s,NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆) 14.84 (CH₃), 39.47 (CH₂), 51.10 (CH₂),51.86 (CH), 56.36 (OCH₃), 57.52 (CH₂), 60.52 (CH₃), 105.88 (CH), 111.59(CH), 123.62 (CH), 125.91 (C), 133.60 (C), 135.58 (C), 136.78 (C),137.70 (C), 150.16 (C), 153.38 (C). LC/MS (ES+) t_(r)=0.95 min, m/z453.38 (M⁺+H). HRMS (ES+) calcd. for C₂₁H₂₉N₂O₇S (M⁺+H) 453.1690, found453.1688. HPLC t_(r)=1.63 min (>97%).

3,4-Dihydro-7-methoxy-3,3-dimethylisoquinolin-6-ol 223

To a flask (ice cooled) containing acetic acid (7.2 ml) was addedpotassium cyanide (1.29 mg, 36.7 mmol) in small portions (CARE: HCN maybe evolved). To this was added a mixture of acetic acid (3.6 ml) andsulfuric acid (7.3 g) slowly with stirring. The ice bath was removed anda solution of 5-(2-hydroxy-2-methylpropyl)-2-methoxyphenol (6.0 mg, 30.6mmol) in acetic acid (4 ml) was added dropwise by syringe over 15 min.The reaction mixture was stirred at rt for 24 h. The reaction mixturewas poured onto ice-water and the aqueous solution neutralised withsodium Carbonate, then extracted with diethyl ether (2×) and ethylacetate (2×) after saturation with sodium chloride. Purification bycolumn chromatography eluting with DCM:EtOAc; 1:1 then EtOAc:MeOH; 4:1afforded the title compound (1.72 g, 30%) as a colourless solid.mp=152-157° C. ¹H NMR (270 MHz; CDCl₃) 1.21 (6H, s, 2×CH₃), 2.62 (2H, s,CH₂), 3.91 (3H, s, OCH₃), 5.69 (1H, brs, OH), 6.60 (1H, s, CH), 6.85(1H, s, CH), 8.07 (1H, s, CH). ¹³C NMR (67.5 MHz; CDCl₃) 28.07 (CH₃),37.96 (CH₂), 54.74 (C(CH₃)₂), 56.04 (CH₃), 110.63 (CH), 113.83 (CH),120.88 (C), 128.02 (C), 144.86 (C), 149.47 (C), 157.19 (C). LC/MS (ES+)t_(r)=0.97 min, m/z 205.9 (M⁺+H). HRMS (ES+) calcd. for C₁₂H₁₅NO₂ (M⁺+H)206.1176, found 206.1169.

1,2,3,4-Tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ol 224

To a solution of 223 (1.67 mg, 8.2 mmol) in ethanol (30 ml) at 0° C. wasadded sodium borohydride (618 mg, 16.3 mmol). The reaction mixture wasstirred at rt for 3 h. Water (50 ml) was added and the aqueous layerneutralised (2M HCl) and extracted with ethyl acetate (3×60 ml). Thecombined organic layers were washed with brine (30 ml), dried (MgSO₄)and concentrated in vacuo to afford the title compound (1.34 mg, 80%) asa white solid. mp=170-173° C. ¹H NMR (270 MHz; DMSO-d₆) 1.04 (6H, s,2×CH₃), 2.42 (2H, s, CH₂), 3.70 (3H, s, OCH₃), 3.72 (2H, s, CH₂), 6.43(1H, s, CH), 6.54 (1H, s, CH), 8.60 (1H, brs, NH). LC/MS (ES+)t_(r)=1.19 min, m/z 208.23 (M⁺+H). HRMS (ES+) calcd. for C₁₂H₁₇NO₂(M⁺+H) 208.1332, found 208.1322.

7-Methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-1,2,3,4-tetrahydro-isoquinoline225

To a solution of 224 (1.25 g, 6 mmol) in DCM (50 ml) was added imidazole(1.73 g, 25.4 mmol) and triisopropylsilyl chloride (2.71 ml, 12.7 mmol).The reaction mixture was stirred at rt for 22 h. Water (30 ml) andChloroform (30 ml) were added. The layers separated and the aqueouslayer extracted with chloroform (3×30 ml). The combined organic layerswere washed with brine (30 ml), dried (MgSO₄) and concentrated in vacuo.Purification by column chromatography eluting with EtOAc:MeOH:TEA;10:1:01 afforded the title compound (1.78 g, 81%) as colourless oil. ¹HNMR (270 MHz; CDCl₃) 1.06 (18H, d, J=6.7 Hz, 6×CH₃CH), 1.14 (6H, s,2×CH₃), 1.14-1.28 (3H, m, 3×CH), 2.51 (2H, s, CH₂), 3.74 (3H, s, OCH₃),3.89 (2H, s, CH₂), 6.46 (1H, s, CH), 6.51 (1H, s, CH). ¹³C NMR (67.5MHz; CDCl₃) 12.95 (CH₃), 18.03 (CH₃), 27.76 (CH), 41.17 (CH₂), 43.97(CH₂), 48.78 (C(CH₃)₂), 55.56 (OCH₃), 112.96 (CH), 117.39 (CH), 126.24(C), 126.92 (C), 143.58 (C), 149.34 (C). LC/MS (ES+) t_(r)=2.65 min, m/z364.36 (M⁺+H).

7-Methoxy-2-(3-methoxy-benzyl)-3,3-dimethyl-6-triisopropylsilanyloxy-1,2,3,4-tetrahydro-isoquinoline226

A mixture of 225 (300 mg, 0.83 mmol), 3-methoxybenzyl chloride (0.13 ml,0.91 mmol) and TEA (0.3 ml, 1.65 mmol) in EtOH (3 ml) was heated in themicrowave at 130° C. for 1.5 h. The reaction mixture was concentrated invacuo. The crude residue was dissolved in EtOAc (30 ml), washed withbrine (20 ml), dried (MgSO₄) and concentrated in vacuo. Purification(flashmaster: 20 g, 100% hex to 50% hex/50% EtOAc and then to 100%EtOAc) afforded the title compound (246 mg, 62%) as colourless oil. ¹HNMR (270 MHz; CDCl₃) 1.04 (18H, d, J=6.7 Hz, CH₃CH), 1.12-1.22 (3H, m,3×SiCHCH₃), 1.17 (6H, s, 2×CH₃), 2.65 (2H, s, CH₂), 3.47 (2H, s, CH₂),3.64 (2H, s, CH₂), 3.74 (3H, s, OCH₃), 3.79 (3H, s, OCH₃), 6.41 (1H, s,CH), 6.48 (1H, s, CH), 6.77 (1H, ddd, J=8.2, 2.2, 1.2 Hz, CH), 6.95-6.98(2H, m, 2×CH), 7.22 (1H, t, J=8.2 Hz, CH). ¹³C NMR (67.5 MHz; CDCl₃)12.38 (CH), 17.49 (CH₃), 23.26 (CH₃), 42.28 (CH₂), 49.64 (CH₂), 52.11(C), 53.22 (CH₂), 54.72 (OCH₃), 55.04 (OCH₃), 111.42 (CH), 111.69 (CH),113.77 (CH), 117.21 (CH), 120.56 (CH), 125.68 (C), 126.34 (C), 128.69(CH), 142.09 (C), 142.89 (C), 148.66 (C), 159.15 (C). LC/MS (ES+)t_(r)=4.54 min, m/z 484.83 (M⁺+H). HRMS (ES+) calcd. for C₂₉H₄₆NO₃Si(M⁺+H) 484.3241, found 484.3242.

7-Methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-2-(3,4,5-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline227

Following the method of 226, the title compound (127 mg, 28%) wasobtained as a colourless oil. ¹H NMR (270 MHz; CDCl₃) 1.04 (18H, d,J=6.7 Hz, 6×CH₃CH), 1.12-1.27 (3H, m, 3×CH), 1.17 (3H, s, CH₃), 2.65(2H, s, CH₂), 3.49 (2H, s, CH₂), 3.60 (2H, s, CH₂), 3.74 (3H, s, OCH₃),3.83 (3H, s, OCH₃), 3.84 (6H, s, 2×OCH₃), 6.44 (1H, s, CH), 6.50 (1H, s,CH), 6.61 (2H, s, 2 X CH). LC/MS (ES+) t_(r)=3.13 min, m/z 544.46(M⁺+H).

2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ol228

To a solution of 226 (237 mg, 0.45 mmol) in THF (10 ml) at 0° C.(ice-bath) was added TBAF (1.0 M in THF, 0.53 ml, 0.53 mmol). Thereaction mixture was stirred at 0° C. for 18 h. water (10 ml) was addedand the aqueous layer was extracted with EtOAc (3×). The combinedorganic layer were washed with brine (10 ml), dried (MgSO₄) andconcentrated in vacuo. Purification (flashmaster: 20 g, 100% hex to 100%EtOAc over 25 min) afforded the title compound (70 mg, 43%) as acolourless oil. ¹H NMR (270 MHz; CDCl₃) 1.18 (6H, s, 2×CH₃), 2.66 (2H,s, CH₂), 3.50 (2H, s, CH₂), 3.65 (2H, s, CH₂), 3.79 (3H, s, OCH₃), 3.83(3H, s, OCH₃), 6.47 (1H, s, CH), 6.52 (1H, s, CH), 6.75-6.79 (1H, m,CH), 6.95-6.97 (2H, m, 2×CH), 7.21 (1H, t, J=8.0 Hz, CH). ¹³C NMR (100MHz; CDCl₃) 23.72 (CH₃), 45.54 (CH₂), 49.97 (CH₂), 52.49 (C), 53.45(CH₂), 55.13 (OCH₃), 55.86 (OCH₃), 110.69 (CH), 111.73 (CH), 111.90(CH), 114.09 (CH), 120.88 (CH), 125.60 (C), 126.86 (C), 129.11 (C),142.41 (C), 143.49 (C), 144.99 (C), 159.59 (C). LC/MS (ES−) t_(r)=1.85min, m/z 326.27 (M−H)⁻. HRMS (ES+) calcd. for C₂₀H₂₆NO₃ (M⁺+H) 328.1907,found 328.1904.

7-Methoxy-3,3-dimethyl-2-(3,4,5-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinolin-6-ol229

TBAF deprotection of 227 (in analogy to the synthesis of 228) affordedthe title compound (95 mg, 71%) as a yellow oil that crystallised ontrituration with DCM/hexane to afford a yellow powder. mp=143-147° C. ¹HNMR (270 MHz; CDCl₃) 1.17 (6H, s, 2×CH₃), 2.66 (2H, s, CH₂), 3.52 (2H,s, CH₂), 3.60 (2H, s, CH₂), 3.82 (3H, s, OCH₃), 3.83 (6H, s, 2×OCH₃),3.84 (3H, s, OCH₃), 5.44 (1H, brs, OH), 6.50 (1H, s, CH), 6.53 (1H, s,CH), 6.60 (2H, s, 2×CH). ¹³C NMR (100 MHz; CDCl₃) 23.82 (CH₃), 42.41(CH₂), 50.02 (CH₂), 52.53 (C), 53.78 (CH₂), 55.88 (OCH₃), 56.05 (OCH₃),60.84 (OCH₃), 105.02 (CH), 110.68 (CH), 111.73 (CH), 125.62 (C), 126.85(C), 136.44 (C), 143.54 (C), 145.02 (C), 153.08 (C). LC/MS (ES−)t_(r)=1.17 min, m/z 386.26 (M−H)⁻. HRMS (ES+) calcd. for C₂₂H₃₀NO₅(M⁺+H) 388.2118, found 388.2111. HPLC t_(r)=2.73 min (>82%).

2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ylsulfamate 230

Sulfamoylation of 226 with H₂NSO₂Cl and DMA as described above affordedthe title compound (86 mg, 89%) as a colourless foam. ¹H NMR (400 MHz;DMSO-d₆) 1.14 (6H, s, 2×CH₃), 2.69 (2H, s, CH₂), 3.43 (2H, s, CH₂), 3.62(2H, s, CH₂), 3.73 (3H, s, OCH₃), 3.75 (3H, s, OCH₃), 6.80 (1H, dd,J=8.0, 2.0 Hz, CH), 6.83 (1H, s, CH), 6.89-6.94 (3H, m, 3×CH), 7.23 (1H,t, J=8.0 Hz, CH), 7.79 (2H, s, NH₂). ¹³C NMR (100 MHz; DMSO-d₆) 42.80(CH₂), 49.42 (CH₂), 52.05 (C), 53.0 (CH₂), 54.94 (OCH₃), 55.79 (OCH₃),111.83 (CH), 112.97 (CH), 114.10 (CH), 120.30 (CH), 120.61 (CH), 125.77(C), 129.25 (CH), 133.04 (C), 136.80 (C), 142.19 (C), 149.88 (C), 159.28(C). LC/MS (ES+) t_(r)=1.14 min, m/z 407.28 (M⁺+H). HRMS (ES+) cald. forC₂₀H₂₇N₂O₅S (M⁺+H) 407.1635, found 407.1636. HPLC t_(r)=2.10 min (>98%).

2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ylsulfamate 231

Sulfamoylation of 299 with H₂NSO₂Cl and DMA as described above affordedthe title compound (58 mg, 73%) as a colourless solid. Purification byprep HPLC eluting with 80% MeOH/20% H₂O afforded a pure sample as acolourless solid. ¹H NMR (400 MHz; DMSO-d₆) 1.14 (6H, s, 2×CH₃), 2.69(2H, s, CH₂), 3.46 (2H, s, CH₂), 3.58 (2H, s, CH₂), 3.63 (3H, s, OCH₃),3.74 (6H, s, 2×OCH₃), 3.75 (3H, s, OCH₃), 6.64 (2H, s, 2×CH), 6.83 (1H,s, CH), 6.92 (1H, s, CH), 7.80 (2H, s, NH₂). LC/MS (ES+) t_(r)=1.31 min,m/z 467.18 (M⁺+H). HRMS (ES+) calcd. for C₂₂H₃₁N₂O₇S (M⁺+H) 467.1847,found 467.1848. HPLC t_(r)=2.0 min (>95%).

(7-Methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-3,4-dihydro-1H-isoquinolin-2-yl)-(3,4,5-trimethoxy-phenyl)-methanone232

To a solution of 225 (300 mg, 0.83 mmol) in DCM (5 ml) was added TEA(0.23 ml, 1.65 mmol) and 3,4,5-trimethoxybenzoyl chloride (228 ml, 0.99mmol). The reaction mixture was stirred at rt for 12 h. Water (10 ml)was added and the aqueous layer was extracted with DCM (3×30 ml). Thecombined organic phases were washed with sat. aq. NaHCO₃ (10 ml) andbrine (10 ml), dried (MgSO₄) and concentrated in vacuo. Purification(flashmaster: 20 g, gradient elution 100% hex to 100% EtOAc over 25 min)afforded the title compound (240 mg, 52%) as a colourless oil. ¹H NMR(270 MHz; CDCl₃) 1.04 (18H, d, J=6.7 Hz, 6×CH₃CH), 1.14-1.24 (3H, m,3×CH), 1.55 (6H, s, 2×CH₃), 2.74 (2H, s, CH₂), 3.80 (3H, s, OCH₃), 3.85(6H, s, 2×OCH₃), 3.86 (3H, s, OCH₃), 4.19 (2H, s, CH₂), 6.53 (1H, s,CH), 6.56 (2H, s, 2×CH), 6.71 (1H, s, CH). LC/MS (ES+) t_(r)=0.2.23 min,m/z 580.24 (M⁺+Na). HRMS (ES+) calcd for C₃₁H₄₇NO₆Si (M⁺+H) 558.3245,found 558.3237.

(3,5-Dimethoxy-phenyl)-(7-methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-3,4-dihydro-1H-isoquinolin-2-yl)-methanone233

Following the method of 232, the title compound (331 mg, 57%) wasobtained as a colourless oil. ¹H NMR (400 MHz; CDCl₃) 1.05 (18H, d,J=7.6 Hz, 6×CH₃), 1.08-1.25 (3H, m, 3×CH), 1.55 (6H, s, 2×CH₃), 2.73(2H, s, CH₂), 3.79 (6H, s, 2×OCH₃), 3.79 (3H, s, OCH₃), 4.17 (2H, s,CH₂), 6.48 (3H, s, 3×CH), 6.52 (1H, s, CH), 6.71 (1H, s, CH). ¹³C NMR(100 MHz; CDCl₃) 12.82 (CH), 17.86 (CH₃), 25.77 (CH₃), 45.24 (CH₂),48.95 (CH₂), 55.47 (OCH₃), 55.53 (OCH₃), 57.18 (C), 101.39 (CH), 104.29(CH), 111.72 (CH), 117.61 (CH), 127.11 (C), 129.40 (C), 140.69 (C),143.81 (C), 150.33 (C), 160.85 (C), 170.56 (C). LC/MS (ES+) t_(r)=2.56min, m/z 550.69 (M⁺+Na) and 528.65 (M⁺+H). HRMS (ES+) calcd. forC₃₀H₄₆NO₅Si (M⁺+H) 528.3140, found 528.3125.

(6-Hydroxy-7-methoxy-3,3-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-(3,4,5-trimethoxy-phenyl)-methanone234

TBAF deprotection of 232 afforded the title compound (151 mg, quant.) asa colourless solid. mp=159-162° C. ¹H NMR (270 MHz; CDCl₃) 1.57 (6H, s,2×CH₃), 2.75 (2H, s, CH₂), 3.85 (6H, s, 2×OCH₃), 3.86 (3H, s, OCH₃),3.90 (3H, s, OCH₃), 4.21 (2H, s, CH₂), 5.55 (1H, s, OH), 6.56 (2H, s,2×CH), 6.61 (1H, s, CH), 6.75 (1H, s, CH). ¹³C NMR (67.5 MHz; CDCl₃)25.93 (CH₃), 45.29 (CH₂), 49.12 (CH₂), 56.21 (OCH₃), 56.29 (OCH₃), 57.27(C(Me)₂), 61.02 (OCH₃), 103.79 (CH), 110.58 (CH), 111.63 (CH), 128.17(C), 134.25 (C), 138.78 (C), 144.23 (C), 146.06 (C), 153.37 (C), 170.81(C). LC/MS (ES−) t_(r)=0.94 min, m/z 400.12 (M−H)⁻. HPLC t_(r)=1.60 min(>99%). Anal. Calcd. for C₂₂H₂₇NO₆: C 65,82, H 6.78, N 3.49. Found: C62.8, H 6.52, N 3.23%.

(3,4-Dihydro-6-hydroxy-7-methoxy-3,3-dimethylisoquinolin-2(1H)-yl)(3,5-dimethoxyphenyl)methanone235

TBAF deprotection of 233 afforded the title compound (112 mg, 56%) as acolourless powder. mp=163-166° C. ¹H NMR (270 MHz; CDCl₃)1.56 (6H, s,2×CH₃), 2.73 (2H, s, CH₂), 3.79 (6H, s, 2×OCH₃), 3.89 (3H, s, OCH₃),4.18 (2H, s, CH₂), 5.56 (1H, s, OH), 6.47 (3H, brs, 3×CH), 6.58 (1H, s,CH), 6.73 (1H, s, CH). ¹³C NMR (67.5 MHz; CDCl₃) 25.92 (CH₃), 45.29(CH₂), 49.09 (CH₂), 55.60 (OCH₃), 56.22 (OCH₃), 57.29 (C), 101.66 (CH),104.24 (CH), 110.48 (CH), 111.79 (CH), 128.03 (C), 128.18 (C), 140.71(C), 144.19 (C), 146.03 (C), 160.96 (C), 170.71 (C). LC/MS (ES−)t_(r)=1.44 min, m/z 370.24 (M−H)⁻. HRMS (ES+) calcd. for C₂₁H₂₆NO₅(M⁺+H) 372.1805, found 372.1803. HPLC t_(r)=2.81 min (>99%).

Sulfamic acid7-methoxy-3,3-dimethyl-2-(3,4,5-trimethoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-6-ylester 236

Sulfamoylation of 234 afforded the title compound (151 mg, 76%) as acolourless solid. mp=172-176° C. ¹H NMR (270 MHz; DMSO-d₆) 1.50 (6H, s,2×CH₃), 2.88 (2H, s, CH₂), 3.71 (3H, s, OCH₃), 3.80 (6H, s, 2×OCH₃),3.81 (3H, s, OCH₃), 4.29 (2H, s, OCH₃), 6.62 (2H, s, 2×CH), 7.08 (1H, s,CH), 7.12 (1H, s, CH), 7.84 (2H, brs, NH₂). ¹³C NMR (67.5 MHz; DMSO-d₆)26.17 (CH₃), 44.63 (CH₂), 48.89 (CH₂), 56.56 (OCH₃), 56.99 (C(Me)₂),60.62 (OCH₃), 104.38 (CH), 113.28 (CH), 120.61 (CH), 127.69 (C), 134.55(C), 136.31 (C), 137.40 (C), 138.51 (C), 151.62 (C), 153.38 (C), 170.01(C). LC/MS (ES−) t_(r)=0.83 min, m/z 479.33 (M−H)⁻. HPLC t_(r)=1.49 min(>99%). Anal. Calcd. for C₂₂H₂₈N₂O₈S: C 54.99, H 5.87, N 5.83. Found: C54.7, H 5.85, N 5.76%.

Sulfamic acid2-(3,5-dimethoxy-benzoyl)-7-methoxy-3,3-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylester 237

Sulfamoylation of 235 afforded the title compound (89 mg, 90%) as acolourless powder. mp=>180° C. dec. ¹H NMR (270 MHz; DMSO-d₆) 1.49 (6H,s, 2×CH₃), 2.86 (2H, s, CH₂), 3.77 (6H, s, 2×OCH₃), 3.80 (3H, s, OCH₃),4.23 (2H, s, CH₂), 6.45 (2H, d, J=2.2 Hz, 2×CH), 6.56 (1H, t, J=2.2 Hz,CH), 7.01 (1H, s, CH), 7.12 (1H, s, CH), 7.84 (2H, s, NH₂). ¹³C NMR(67.5 MHz; DMSO-d₆) 26.11 (CH₃), 44.56 (CH₂), 48.84 (CH₂), 55.97 (OCH₃),56.56 (OCH₃), 57.03 (C), 101.69 (CH), 104.57 (CH), 113.28 (CH), 120.57(CH), 127.49 (C), 136.31 (C), 137.37 (C), 141.15 (C), 151.67 (C), 161.01(C), 169.88 (C). LC/MS (ES+) t_(r)=1.29 min, m/z 473.28 (M⁺+Na). HRMS(ES+) calcd. for C₂₁H₂₇₂O₇S (M⁺+H) 451.1533, found 451.1519. HPLCt_(r)=1.55 min (>99%).

3,4-Dihydro-7-methoxy-1,3,3-trimethylisoquinolin-6-ol 238

To a flask (ice cooled) containing acetic acid (1.2 ml) was added5-(2-hydroxy-2-methylpropyl)-2-methoxyphenol (500 mg, 2.5 mmol) andacetonitrile (0.27 ml, 5.1 mmol). To this was added sulfuric acid (1.2ml) slowly with stirring. The reaction mixture was allowed to warm to rtand stirred for 4 h. The reaction mixture was poured onto ice-water andthe aqueous solution neutralised with sodium C(Ar)bonate, then extractedwith diethyl ether (2×) and ethyl acetate (2×) after saturation withsodium chloride. Purification (flashmaster: 20 g, 100% DCM to 100%EtOAc, then 30% MeOH/70% EtOAc) afforded the title compound (324 mg,56%) as a pale brown solid. mp=160° C. dec. ¹H NMR (270 MHz; CDCl₃) 1.18(6H, s, 2×CH₃), 2.28 (3H, s, CH₃), 2.59 (2H, s, CH₂), 3.91 (3H, s,OCH₃), 6.60 (1H, s, CH), 7.07 (1H, s, CH). ¹³C NMR (67.5 MHz; CDCl₃)23.21 (CH₃), 28.02 (2×CH₃), 38.81 (CH₂), 53.78 (C(CH₃)₂), 55.98 (CH₃),110.47 (CH), 112.35 (CH)<121.96 (C), 128.86 (C), 144.35 (C), 148.88 (C),161.39 (C N). LC/MS (ES+) t_(r)=1.2 min, m/z 219.95 (M⁺+H).

1,2,3,4-Tetrahydro-7-methoxy-1,3,3-trimethylisoquinolin-6-ol 239

Following the method for 224, the title compound (228 mg, 78%) wasobtained as a beige solid. mp=80-185° C. ¹H NMR (270 MHz; DMSO-d₆) 0.97(3H, s, CH₃), 1.15 (3H, s, CH₃), 1.26 (3H, d, J=6.7 Hz, CH₃CH), 2.35(1H, brd, J=15.3 Hz, CHH), 2.55 (1H, d, J=15.3 Hz, CHH), 3.70 (3H, s,OCH₃), 3.87 (1H, q, J=6.7 Hz, CHCH₃), 6.53 (1H, s, CH), 6.59 (1H, s,CH). LC/MS (ES+) t_(r)=1.21 min, m/z 222.09 (M⁺+H). HRMS (ES+) calcd.for C₁₃H₂₀NO₂ (M⁺+H) 222.1489, found 222.1486.

7-Methoxy-1,3,3-trimethyl-6-triisopropylsilanyloxy-1,2,3,4-tetrahydro-isoquinoline240

239 (183 mg, 0.83 mmol), TIPS-Cl (237 mg, 3.5 mmol) and imidazole (237mg, 3.5 mmol) in DCM (10 ml) were stirred at rt for 24 h. The reactionmixture was quenched with water (5 ml) and extracted with DCM (3×10 ml).The combined organic extracts were washed with brine (10 ml), dried(MgSO₄) and concentrated in vacuo. Purification (personal flashmaster:20 g, EtOAc:MeOH:TEA; 100:10:1) afforded the title compound (332 mg) asa yellow oily solid. ¹H NMR (270 MHz; CDCl₃) 1.07 (18H, d, J=6.4 Hz,6×CH ₃CH), 1.08 (3H, s, CH₃), 1.15-1.28 (3H, m, 3×CHCH₃), 1.25 (3H, s,CH₃), 1.21 (3H, d, J=6.4 Hz, CH ₃CH), 2.44 (1H, d, J=15.8 Hz, CHH), 2.65(1H, d, J=15.8 Hz, CHH), 3.74 (3H, s, OCH₃), 4.0 (1H, q, J=6.4 Hz,CHCH₃), 6.46 (1H, s, CH), 6.67 (1H, s, CH). LC/MS (ES+) t_(r)=1.8 min,m/z 378.24 (M⁺+H).

7-Methoxy-2-(3-methoxy-benzyl)-1,3,3-trimethyl-6-triisopropylsilanyloxy-1,2,3,4-tetrahydro-isoquinoline241

To a solution of 240 (170 mg, 0.45 mmol) in acetone (1.5 ml) was addedcesium C(Ar)bonate (162 mg, 0.5 mmol) followed by 3-methoxy benzylbromide (0.063 ml, 0.54 mmol). The reaction mixture was stirred at rtfor 23 h. The resulting solution was diluted with water and extractedwith ethyl acetate (3×). The combined organic phases were washed withbrine, dried (MgSO₄) and concentrated in vacuo. Purification(Flashmaster; 10 g, 100% hex to 95% hex:5% EtOAc over 25 min) affordedthe title compound (79 mg, 35%) as a colourless oil. ¹H NMR (270 MHz;CDCl₃) 0.94 (3H, s, CH₃), 1.07 (18H, d, J=6.7 Hz, 6×SiCHCH₃), 1.09 (3H,s, CH₃), 1.15-1.29 (3H, m, 3×CH), 1.20 (3H, d, J=6.2 Hz, CH ₃CH), 2.37(1H, d, J=15.3 Hz, one of CH₂), 2.94 (1H, d, J=15.3 Hz, one of CH₂),3.50 (1H, d, J=17.3 Hz, one of CH₂), 3.71 (1H, q, J=6.2 Hz, CHCH₃), 3.76(3H, s, OCH₃), 3.79 (3H, s, OCH₃), 4.09 (1H, d, J=17.3 Hz, one of CH₂),6.48 (1H, s, CH), 6.59 (1H, s, CH), 6.71 (1H, dd, J=7.7, 2.2 Hz, CH),7.0 (1H, d, J=7.7 Hz, CH), 7.09 (1H, brs, CH), 7.19 (1H, t, J=7.9 Hz,CH). ¹³C NMR (100 MHz; CDCl₃) 12.85 (CH₃), 17.92 (CH₃), 18.69 (CH₃),24.35 (CH₃), 30.03 (CH₃), 44.29 (CH₂), 53.29 (CH₂), 53.72 (C), 55.08(OCH), 55.47 (OCH₃), 57.40 (OCH₃), 111.06 (CH), 111.84 (CH), 112.92(CH), 118.13 (CH), 119.34 (CH), 126.70 (C), 128.81 (CH), 132.34 (C),143.23 (C), 146.35 (C), 148.81 (C), 159.46 (C). LC/MS (ES+) t_(r)=7.09min, m/z 498.42 (M⁺+H). HPLC t_(r)=7.03 min (>98%).

2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-1,3,3-trimethylisoquinolin-6-ol242

TBAF deprotection of 241 afforded the title compound (28 mg, 54%) as acolourless oil that turned orange on standing. ¹H NMR (270 MHz; CDCl₃)0.97 (3H, s, CH₃), 1.12 (3H, s, CH₃), 1.24 (3H, d, J=6.4 Hz, CH₃CH),2.39 (1H, d, J=15.2 Hz, one of CH₂), 2.95 (1H, d, J=15.2 Hz, one ofCH₂), 3.52 (1H, d, J=17.0 Hz, one of CH₂), 3.75 (1H, q, J=6.4 Hz, CH),3.79 (3H, s, OCH₃), 3.86 (3H, s, OCH₃), 4.1 (1H, d, J=17.0 Hz, of CH₂),5.45 (1H, s, OH), 6.52 (1H, s, CH), 6.67 (1H, s, CH), 6.72 (1H, dd,J=8.0, 2.4 Hz, CH), 7.0 (1H, d, J=7.7 Hz, CH), 7.09 (1H, s, CH), 7.20(1H, t, J=7.9 Hz, CH). LC/MS (ES+) t_(r)=1.27 min, m/z 342.21 (M⁺+H).HPLC t_(r)=2.92 min (>96%).

6-(Benzyloxy)-3,4-dihydro-7-methoxy-1,3,3-trimethylisoquinoline 243

To a solution of 239 (970 mg, 4.4 mmol) in acetone (10 ml) was addedpotassium C(Ar)bonate (3.06 g, 22.0 mmol), benzyl bromide (1.05 ml, 8.8mmol) and tetrabutyl ammonium iodide (163 mg, 0.44 mmol). The reactionmixture was heated at 55° C. for 60 h. The reaction mixture was cooledto rt, water (20 ml) was added and the aqueous layer was extracted withethyl acetate (3×30 ml). The combined organic phases were dried (MgSO₄)and concentrated in vacuo. Purification by flash column chromatographyeluting with EtOAc then EtOAc:MeOH:TEA; 10:1:0.1 afforded the titlecompound (882 mg, 64%) as a pale orange solid. mp=87.9-90° C. ¹H NMR(270 MHz; CDCl₃) 1.16 (6H, s, 2×CH₃), 2.22 (3H, s, CH₃), 2.59 (2H, s,CH₂), 3.90 (3H, s, OCH₃), 5.13 (2H, s, CH₂Ph), 6.63 (1H, s, CH), 7.0(1H, s, CH), 7.27-7.46 (5H, m, 5×CH, phenyl). ¹³C NMR (67.5 MHz; CDCl₃)23.54 (CH₃), 28.15 (2×CH₃), 38.70 (CH₂), 53.65 (C(CH₃)), 56.07 (OCH₃),71.87 (CH₂Ph), 111.40 (CH), 112.57 (CH), 121.49 (C), 127.58 (CH), 128.08(CH), 128.68 (CH), 130.78 (C), 137.15 (C), 146.33 (C), 151.79 (C),160.65 (C). LC/MS (ES+) t_(r)=2.5 min, m/z 310.05 (M⁺+H). HRMS (ES+)calcd. for C₂₀H₂₄NO₂ (M⁺+H) 310.1802, found 310.1801.

6-(Benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-1,3,3-trimethylisoquinoline244

Sodium borohydride reduction following the method described for thesynthesis of 224 afforded the title compound (494 mg, 91%) as a paleyellow solid. mp ¹H NMR (270 MHz; CDCl₃) 1.06 (3H, s, CH₃), 1.22 (3H, s,CH₃), 1.32 (3H, d, J=6.4 Hz, CH₃CH), 2.46 (1H, d, J=15.8 Hz, one ofCH₂), 2.63 (1H, d, J=15.8 Hz, one of CH₂), 3.84 (3H, s, OCH₃), 3.98 (1H,q, J=6.4 Hz, CHCH₃), 5.10 (2H, s, CH₂Ph), 6.53 (1H, s, CH), 6.68 (1H, s,CH), 7.25-7.45 (5H, m, 5×CH, phenyl). ¹³C NMR (67.5 MHz; CDCl₃) 22.72(CH₃), 24.21 (CH₃), 31.80 (CH₃), 42.03 (CH₂), 47.68 (CH), 49.02 (C),55.90 (OCH₃), 71.40 (CH₂Ph), 111.72 (CH), 112.39 (CH), 127.27 (C),127.37 (CH), 127.73 (CH), 128.45 (CH), 130.98 (C), 137.37 (C), 146.26(C), 148.07 (C). LC/MS (ES+) t_(r)=1.06 min, m/z 312.10 (M⁺+H). HRMS(ES+) calcd. for C₂₀H₂₆NO₂ (M⁺+H) 312.1958, found 312.1959.

(6-(Benzyloxy)-3,4-dihydro-7-methoxy-1,3,3-trimethylisoquinolin-2(1H)-yl)-(3,4,5-trimethoxyphenyl)methanone245

To a solution of 244 (467 mg, 1.5 mmol) in DCM (10 ml) was addedtriethyl amine (0.42 ml) and 3,4,5-trimethoxybenzoyl chloride (520 mg,2.3 mmol). The reaction mixture was stirred at rt for 21 h. TLC analysisindicated the presence of starting material so the reaction mixture washeated in the microwave for 5 min at 60° C. and for 15 min at 80° C. Afurther 0.5 eq of benzoyl chloride was added and the reaction mixturewas heated in the microwave at 80° C. for 15 min. Water (20 ml) wasadded, the layers separated and the aqueous layer extracted with DCM(3×60 ml). The combined organic phases were washed with sat. aq. sodiumhydrogen C(Ar)bonate (60 ml) and brine (60 ml), dried (MgSO₄) andconcentrated in vacuo. Purification (flashmaster: 20 g, EtOAc/hex thenHex/DCM) afforded the title compound (440 mg, 58%) as a colourless foam.mp 175-177° C. ¹H NMR (270 MHz; CDCl₃) 1.32 (3H, d, J=6.9 Hz, CH ₃CH),1.39 (3H, s, CH₃), 1.87 (3H, s, CH₃), 2.53 (1H, d, J=15.3 Hz, one ofCH₂), 3.27 (1H, d, J=15.3 Hz, one of CH₂), 3.82 (6H, s, 2×OCH₃), 3.86(3H, s, OCH₃), 3.88 (3H, s, OCH₃), 4.69 (1H, q, J=6.9 Hz, CHCH₃), 5.04(2H, ABq, J=12.1 Hz, CH ₂Ph), 6.47 (3H, s, 3×CH), 6.75 (1H, s, CH),7.25-7.41 (5H, m, 5×CH, phenyl). ¹³C NMR (100 MHz; CDCl₃) 23.43 (CH₃),25.28 (CH₃), 29.40 (CH₃), 44.18 (CH₂), 56.18 (4×OCH₃), 57.68 (C), 60.92(CH), 71.38 (CH₂), 102.51 (CH), 111.45 (CH), 112.36 (CH), 127.09 (C),127.28 (CH), 127.87 (CH), 128.49 (CH), 130.61 (C), 135.07 (C), 136.09(C), 137.89 (C), 146.88 (C), 149.06 (C), 153.41 (C), 170.97 (C). LC/MS(ES+) t_(r)=1.03 min, m/z 528.27 (M⁺+Na). HPLC t_(r)=2.38 min (>99%).Anal. Calcd. for C₃₀H₃₅NO₆: C 71.27, H 6.98, N 2.77. Found: C 71.1, H6.99, N 2.70%.

(3,4-Dihydro-6-hydroxy-7-methoxy-1,3,3-trimethylisoquinolin-2(1H)-yl)(3,4,5-trimethoxyphenyl)methanone246

Method as for 217 afforded the title compound (252 mg, 74%) as acolourless solid. mp=198-200° C. ¹H NMR (270 MHz: CDCl₃) 1.34 (3H, d,J=6.9 Hz, CH ₃CH),1.39 (3H, s, CH₃), 1.86 (3H, s, CH₃), 2.53 (1H, d,J=1.53 Hz, one of CH₂), 3.27 (1H, d, J=15.3 Hz, one of CH₂), 3.84 (6H,s, 2×OCH₃), 3.86 (3H, s, OCH₃), 3.88 (3H, s, OCH₃), 4.74 (1H, q, J=6.9Hz, CHCH₃), 5.56 (1H, d, J=0.6 Hz, OH), 6.48 (2H, s, 2×CH), 6.50 (1H, s,CH), 6.70 (1H, s, CH). ¹³C NMR (100 MHz; CDCl₃) 23.28 (CH₃), 25.22(CH₃), 29.37 (CH₃), 44.18 (CH₂), 56.07 (OCH₃), 56.11 (OCH₃), 56.17(OCH₃), 57.68 (C), 60.90 (CH), 102.56 (CH), 110.98 (CH), 111.36 (CH),125.67 (C), 131.38 (C), 134.94 (C), 137.97 (C), 144.22 (C), 145.71 (C),153.40 (C), 171.03 (C). LC/MS (ES−) t_(r)=0.91 min, m/z 414.27 (M⁺+H).HPLC t_(r)=2.70 min (>99%).

Sulfamic acid7-methoxy-1,3,3-trimethyl-2-(3,4,5-trimethoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-6-ylester 247

Sulfamoylation as for 220 afforded the title compound (59 mg, 62%) ascolourless solid. mp=170-173° C. ¹H NMR (400 MHz; DMSO-d₆) 1.32 (3H, s,CH₃), 1.33 (3H, d, J=7.2 Hz, CH ₃CH), 1.80 (3H, s, CH₃), 2.75 (1H, d,J=15.4 Hz, one of CH₂), 3.30 (1H, d, J=15.4 Hz, one of CH₂), 3.70 (3H,s, OCH₃), 3.78 (6H, s, OCH₃), 3.80 (3H, s, OCH₃), 4.73 (1H, q, J=7.2 Hz,CHCH₃), 6.51 (2H, s, 2×CH), 6.98 (1H, s, CH), 7.09 (1H, s, CH), 7.84(2H, s, NH₂). ¹³C NMR (100 MHz; DMSO-d₆) 22.97 (CH₃), 25.17 (CH₃), 28.89(CH₃), 43.18 (CH₂), 55.10 (OCH₃), 55.05 (OCH₃), 56.08 (OCH₃), 56.88 (C),60.13 (CH), 102.67 (CH), 113.36 (CH)<120.07 (CH), 130.51 (C), 133.35(C), 134.84 (C), 136.97 (C), 137.27 (C), 150.97 (C), 153.04 (C), 169.79(C). LC/MS (ES−) t_(r)=1.27 min, m/z 493.25 (M−H⁻). HPLC t_(r)=2.44 min(>99%). Anal. Calcd. for C₂₃H₃₀N₂O₈S: C 55.86, H 6.11, N 5.66. Found C56.1, H 6.31, N 5.50%.

6-(Benzyloxy)-3,4-dihydro-7-methoxy-1-methylisoquinoline 249

A mixture of 248 (2.68 mg, 8.9 mmol) and phosphorus oxychloride (8.23ml, 53.7 mmol) in toluene (50 ml) was heated under reflux for 3 h. Thereaction mixture was cooled to rt, iced water (50 ml) was added andchloroform. The layers were separated and the aqueous layer was basifiedto pH 9 and extracted with chloroform (2×). The combined organic layerswere washed with water, dried (MgSO₄) and concentrated in vacuo toafford the title compound (949 mg, 38%) a yellow oil. ¹H NMR (270 MHz;CDCl₃) 2.51 (3H, s, CH₃), 2.68 (2H, t, J=7.7 Hz, CH₂), 3.66 (2H, td,J=7.7, 1.2 Hz, CH₂), 3.90 (3H, s, OCH₃), 5.19 (2H, s, CH₂), 6.72 (1H, s,CH), 7.04 (1H, s, CH), 7.28-7.44 (5H, m, 5×CH, phenyl). LC/MS (ES+)t_(r)=0.57 min, m/z 282.06 (M⁺+H).

6-(Benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinoline 250

To a solution of 249 (949 mg, 3.4 mmol) in EtOH (15 ml) at 0° C. wasadded sodium borohydride (256 mg, 6.8 mmol) portionwise. The reactionmixture was stirred at rt for 1.5 h. Water (100 ml) was added and theaqueous layer was neutralised. The aqueous layer was saturated withsodium chloride and extracted with EtOAc (3×100 ml). The combinedorganic layers were washed with sat. aq. sodium hydrogen C(Ar)bonate(100 ml), dried (MgSO₄) and concentrated in vacuo to afford the titlecompound (600 mg, 63%) a yellow oil. ¹H NMR (400 MHz; DMSO-d₆) 1.58 (3H,d, J=6.4 Hz, CH₃CH), 2.50 (2H, s, CH₂), 2.82-2.95 (2H, m, CH₂), 3.76(3H, s, OCH₃), 4.42 (1H, q, J=6.4 Hz, CH₃CH), 5.06 (2H, s, CH₂Ph), 6.86(1H, s, CH), 6.88 (1H, s, CH), 7.31-7.44 (5H, m, 5×CH, phenyl), 9.40(1H, brs, NH). LC/MS (ES+) t_(r)=0.73 min, m/z 284.13 (M⁺+H).

2-(3,4,5-Trimethoxybenzyl)-6-(benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinoline251

A solution of 250 (170 mg, 0.6 mmol), 3,4,5-trimethoxybenzyl chloride(156 mg, 0.72 mmol) and triethyl amine (0.17 ml, 1.2 mmol) in EtOH (3ml) was heated in the microwave at 130° C. for 1.5 h, then at 170° C.for 30 min. The reaction mixture was concentrated in vacuo. Purification(flashmaster: 20 g, gradient elution 100% hex to 50% hex:50% EtOAc over25 min) afforded The title compound (58 mg, 21%) as a colourless oil. ¹HNMR (270 MHz; CDCl₃) 1.36 (3H, d, J=6.7 Hz, CH₃CH), 2.47-2.55 (1H, m,one of CH₂), 2.67-2.84 (2H, m, 2×CH, CH₂), 2.98-3.07 (1H, m, one ofCH₂), 3.59-3.73 (2H, m, CH₂), 3.83 (9H, s, 3×OCH₃), 3.88 (3H, s, OCH₃),5.09 (2H, s, CH₂), 6.56-6.62 (4H, m, 4×CH), 7.27-7.44 (5H, m, 5×CH,phenyl). LC/MS (ES+) t_(r)=1.26 min, m/z 464.34 (M⁺+H).

2-(3-Methoxybenzyl)-6-(benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinoline252

Following the method of 251, the title compound (254 mg, 62%) wasobtained as a colourless oil. ¹H NMR (400 MHz; CDCl₃) 1.18 (3H, d, J=6.8Hz, CH ₃CH), 2.49-2.55 (1H, m, one of CH₂), 2.66-2.82 (2H, m, CH₂),3.0-3.07 (1H, m, one of CH₂), 3.72-3.81 (2H, m, CH₂), 3.80 (3H, s,OCH₃), 3.81-3.86 (1H, m, overlapping signals, CHCH₃), 3.84 (3H, s,OCH₃), 5.11 (2H, s, CH₂Ph), 6.56 (1H, s, CH), 6.61 (1H, s, CH), 6.80(1H, dd, J=8.2, 1.8 Hz, CH), 6.95-6.98 (2H, m, 2×CH), 7.23 (1H, t, J=8.0Hz, CH), 7.25-7.45 (5H, m, 5×CH). ¹³C NMR (100 MHz; CDC₃) 19.79 (CH₃),26.64 (CH₂), 43.75 (CH₂), 55.18 (OCH₃), 55.77 (CH), 56.12 (OCH₃), 57.99(CH₂), 70.96 (CH₂), 110.96 (CH), 112.39 (CH), 113.92 (CH), 113.93 (CH),121.0 (CH), 126.14 (C), 127.26 (CH), 127.71 (CH), 128.47 (CH), 129.12(CH), 132.77 (C), 137.31 (C), 141.35 (C), 146.51 (C), 147.76 (C), 159.64(C). LC/MS (ES+) t_(r)=1.37 min, m/z 404.06 (M⁺+H). HRMS (ES+) calcd.for C₂₆H₃₀NO₃ (M⁺+H) 404.2220, found 404.2224.

2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinolin-6-ol253

Hydrogenation of 252 the title compound (150 mg, 70%) was obtained ayellow foam. mp=97-99° C. ¹H NMR (270 MHz; CDCl₃) 1.36 (3H, d, J=6.6 Hz,CH ₃CH), 2.40-2.58 (1H, m, one of CH₂), 2.67-2.87 (2H, m, two of CH₂),3.02-3.11 (1H, m, one of CH₂), 3.72 (2H, ABq, J=13.5 Hz, CH₂), 2.78-3.83(1H, m, overlapping signals, CHCH₃), 3.80 (3H, s, OCH₃), 3.83 (3H, s,OCH₃), 6.51 (1H, s, CH), 6.63 (1H, s, CH), 6.80 (1H, dd, J=8.2, 2.7 Hz,CH), 6.95-6.99 (2H, m, 2×CH), 7.23 (1H, t, J=7.7 Hz, CH). ¹³C NMR (67.5MHz; CDCl₃) 20.24 (CH₃), 26.40 (CH₂), 43.83 (CH₂), 55.32 (OCH₃), 55.86(CH), 56.06 (OCH₃), 58.07 (CH₂), 109.68 (CH), 112.58 (CH), 114.04 (CH),114.35 (CH), 126.94 (C), 129.25 (CH), 131.64 (C), 141.42 (C), 143.84(C), 144.99 (C), 159.76 (C). LC/MS (ES+) t_(r)=1.06 min, m/z 314.18(M⁺+H). HRMS (ES+) calcd. for C₁₉H₂₄O₃ (M⁺+H) 314.1751, found 314.1742.HPLC t_(r)=2.65 min (>97%).

2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinolin-6-ol254

Hydrogenation of 251 gave the title compound (72 mg, 65%) as a paleyellow foam. ¹H NMR (270 MHz; CDCl₃) 1.35 (3H, d, J=6.6 Hz, CH₃CH),2.50-2.57 (1H, m, one of CH₂), 2.69-2.85 (2H, m, CH₂), 3.02-3.11 (1H, m,one of CH₂), 3.67 (2H, ABq, J=13.9 Hz, CH₂), 3.77-3.84 (1H, m,overlapping signals, CHCH₃), 3.84 (12H, s, 4×OCH₃), 6.51 (1H, s, CH),6.62 (2H, s, 2×CH), 6.64 (1H, s, CH). LC/MS (ES+) t_(r)=0.95 min, m/z374.21 (M⁺+H). HRMS (ES+) calcd. for C₂₁H₂₈NO₅ (M⁺+H) 374.1962, found374.1959. HPLC t_(r)=2.48 min (>98%).

2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinolin-6-ylsulfamate 255

Sulfamoylation of 253 (carried out as described above) afforded thetitle compound (127 mg, 77%) as a pale yellow foam. ¹H NMR (400 MHz;DMSO-d₆) 1.31 (3H, d, J=6.4 Hz, CH ₃CH), 2.50-2.54 (1H, m, one of CH₂),2.63-2.66 (1H, m, one of CH₂), 2.73-2.81 (1H, m, one of CH₂), 2.93-2.98(1H, m, one of CH₂), 3.69 (2H, ABq, J=14.0 Hz, CH₂), 3.73 (3H, s, OCH₃),3.74 (3H, s, OCH₃), 3.80 (1H, q, J=6.5 Hz, CHCH₃), 6.81 (1H, dd, J=7.8,2.2 Hz, CH), 6.86 (1H, s, CH), 6.92-6.93 (2H, m, 2×CH), 7.01 (1H, s,CH), 7.24 (1H, t, J=8.0 Hz, CH), 7.86 (2H, s, NH₂). ¹³C NMR (100 MHz;DMSO-d₆) 19.17 (CH₃), 25.88 (CH₂), 42.99 (CH₂), 54.95 (OCH₃), 55.19(CH), 55.86 (OCH₃), 57.21 (CH₂), 112.10 (CH), 112.30 (CH), 113.70 (CH),120.56 (CH), 122.86 (CH), 125.75 (C), 129.30 (CH), 136.92 (C), 139.07(C), 141.14 (C), 146.69 (C), 159.37 (C). LC/MS (ES+) t_(r)=1.70 min, m/z393.17 (M⁺+H). HRMS calcd. for C₁₉H₂₅N₂O₅S (M⁺+H) 393.1479, found393.1476. HPLC t_(r)=2.05 min (>94%).

2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-1-methylisoquinolin-6-ylsulfamate 256

Sulfamoylation of 254 (carried out as described above) afforded thetitle compound (75 mg, 95%) as a yellow foam. ¹H NMR (400 MHz; DMSO-d₆)1.33 (3H, d, J=6.8 Hz, CH ₃CH), 2.50-2.55 (1H, m, one of CH₂), 2.61-2.82(2H, m, two of CH₂), 2.91-3.11 (1H, m, one of CH₂), 3.64 (3H, s, OCH₃),3.65 (2H, s, CH₂), 3.74 (9H, s, 3×OCH₃), 3.82 (1H, q, J=6.8 Hz, CHCH₃),6.67 (2H, s, 2×CH), 6.88(1H, s, CH), 7.02 (1H, s, CH), 7.87 (2H, s,NH₂). ¹³C NMR (100 MHz; DMSO-d₆) 19.39 (CH₃), 25.73 (CH₂), 42.81 (CH₂),55.19 (CH), 55.76 (OCH₃), 55.87 (OCH₃), 57.36 (CH₂), 59.97 (OCH₃),104.99 (CH), 112.17 (CH), 122.85 (CH), 125.75 (C), 135.20 (C), 136.10(C), 136.94 (C), 139.04 (C), 149.69 (C), 152.85 (C). LC/MS (ES+)t_(r)=0.89 min, m/z 453.15 (M⁺+H). HRMS (ES+) calcd. for C₂₁H₂₉N₂O₇S(M⁺+H) 453.1690, found 453.1695. HPLC t_(r)=1.85 min (>94%).

2-Benzyloxy-1-methoxy-4-(2-nitro-but-1-enyl)-benzene 257

3-Benzyloxy-4-methoxybenzaldehyde (24.23 g, 100 mmol) and ammoniumacetate (7.73 g, 100 mmol) were covered with 1-nitropropane (90 mL, 1008mmol) and heated to 160° C. for 22 h. The reaction mixture was thencooled to room temperature and the excess of 1-nitropropane was removedin vacuo. The residue was dissolved in ethyl acetate (300 mL), washedwith water (100 mL), brine (50 mL), dried (MgSO₄), filtered andconcentrated in vacuo. The residue was boiled up in ethanol (100 mL).After cooling to room temperature the yellow precipitate was collectedon a sinter funnel and washed with ethanol (4×30 mL). The solid wasdried in vacuo to give the title compound as yellow powder (14.07 g,44%). ¹H NMR (270 MHz, CDCl₃) δ 1.14 (3H, t, J 7.3, CH₂CH₃), 2.71 (2H,q, J 7.4, CH₂CH₃), 3.93 (3H, s, OCH₃), 5.19 (2H, s, OCH₂Ph), 6.91 (1H,d, J 1.9, CH), 6.94 (1H, d, J 8.5, CH), 7.05 (1H, dd, J 8.4, CH),7.25-7.48 (5H, m, OCH₂C₆H₅), 7.91 (1H, s, HC═CNO₂).

2-Benzyloxy-1-methoxy-4-(2-nitro-butyl)-benzene 258

Finely powdered sodium borohydride (3.38 g, 89.3 mmol) was covered withTHF (40 mL) and ethanol (40 mL) and cooled to 0° C. 257 (13.95 g, 44.5mmol) was dissolved in THF (120 mL) and added slowly over 2 h viadropping funnel. The reaction mixture was stirred for 4 h at 0° C. andthen for 60 h at room temperature. Hydrochloric acid (2M, 45 mL) wasadded very carefully. The two layers were separated and the organiclayer was concentrated in vacuo. The crude product was purified by flashcolumn chromatography (SiO₂: 100 g, hexane/ethyl acetate 90:10) to givethe title compound (8.83 g, 62%) as yellow solid. ¹H NMR (270 MHz,CDCl₃) δ 0.91 (3H, t, J 7.4, CH₂CH₃), 1.62-1.79 (1H, m, one ofCHCH₂CH₃), 1.81-2.00 (1H, m, one of CHCH₂CH₃), 2.88 (1H, dd, J 14.3,6.0, one of ArCH₂CH), 3.12 (1H, dd, J 14.3, 8.3, one of ArCH₂CH), 3.84(3H, s, OCH₃), 4.42-4.55 (1H, m, CHNO₂), 5.11 (2H, OCH₂Ph), 6.65 (1H, d,J 1.9, CH), 6.69 (1H, dd, J 8.2, 1.9, CH), 6.80 (1H, d, J8.0, CH),7.25-7.45 (5H, m, OCH₂C₆H₅).

N-[1-(3-Benzyloxy-4-methoxy-benzyl)-propyl]-acetamide 259

Raney-Nickel (3.82 g, 50% in water, ˜32.5 mmol) and a large heavy ovalstirring bar were placed in a 500 mL RBF. The water was removed viapipette and the Raney-Nickel was washed with methanol (2×10 mL). Thenmethanol (100 mL) and 258 (7.88 g, 25.0 mmol) were added and the mixturewas cooled to 0° C. Hydrazine hydrate (6.30 g, 126 mmol) was addeddropwise via syringe. The reaction mixture was stirred for 30 min at 0°C., then for 7 h at 50° C. The mixture was passed through a sinterfunnel with celite to remove the Raney-Nickel. The sinter was washedwith methanol (4×20 mL). The combined filtrates were concentrated invacuo to receive the crude amine as brownish green oil (7.72 g) whichwas used without further purification. The crude amine (7.41 g, max.24.0 mmol) was dissolved in dichloromethane (80 mL) and cooled to 0° C.Triethylamine (3.68 g, 36.4 mmol) was added, then acetic anhydride (2.96g, 29.0 mmol) added dropwise via syringe. The reaction mixture wasstirred for 4 h. Water (40 mL) and hydrochloric acid (5M, 10 mL) wereadded and the layers separated. The aqueous layer was extracted withdichloromethane (2×100 mL). The combined organic layers were washed withbrine (80 mL), dried (MgSO₄), filtered and concentrated in vacuo to givethe title compound (8.73 g, >99%) as beige solid. ¹H NMR (270 MHz,CDCl₃) δ 0.83 (3H, t, J 7.4, CH₂CH₃), 1.09-1.27 (1H, m, one of CH₂CH₃),1.32-1.50 (1H, m, one of CH₂CH₃), 1.87 (3H, s, NCOCH₃), 2.64 (2H, d, J6.3, ArCH₂CH), 3.85 (3H, s, OCH₃), 3.89-4.07 (1H, m, ArCH₂CH), 5.08 (1H,d, br, J 8.8, NH), 5.13 (2H, s, OCH₂Ph), 6.63-6.72 (2H, m, 2×CH),6.77-6.82 (1H, m, CH), 7.24-7.44 (5H, m, OCH₂C₆H₅).

2-Acyl-3-ethyl-6-benzyloxy-7-methoxytetrahydroisoquinoline 260

N-[1-(3-Benzyloxy-4-methoxy-benzyl)-propyl]acetamide 259 (8.70 g, max.23.0 mmol), para-toluenesulfonic acid monohydrate (2.12 g, mmol) andpara-formaldehyde (220 mg, mmol) were covered with toluene (140 mL) andheated to 140° C. for 22 h. The solvent was removed in vacuo to obtainthe crude product (8.0 g) which appeared to be a mixture of product(˜60%) and starting material (˜40%). The crude product was dry-loadedonto SiO₂ (30 g) and purified by flash column chromatography (SiO₂: 120g, ethyl acetate 100%) to give a mixture of the title compound andstarting material. The whole mixture was treated again withpara-toluenelsulfonic acid monohydrate (218 mg, mmol) andpara-formaldehyde (2.10 g, mmol) in toluene (140 mL) at 120° C. for 16h. The mixture was concentrated in vacuo, water (100 mL) added andextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water (50 mL) and brine (2×20 mL), dried (MgSO₄),filtered and concentrated in vacuo to give the title compound (6.33 g,81%) as viscous orange oil. ¹H NMR (270 MHz, CDCl₃) δ 0.86 (3H, t, J7.5, CH₂CH₃), 1.23-1.64 (2H, m, CH₂CH₃), 2.16 (3H, s, NCOCH₃), 2.44-2.61(1H, m, one of ArCH₂CH), 2.80-3.06 (1H, m, one of ArCH₂CH), 3.82 (3H, s,OCH₃), 3.92-4.03 (1H, m, CHN), 4.33 (1H, d, J 16.2, one of ArCH₂N), 4.55(1H, d, J 16.2, one of ArCH₂N), 5.08 (2H, s, OCH₂Ph), 6.53-6.64 (2H, m,2×CH), 7.18-7.44 (5H, m, OCH₂C₆H₅).

3-Ethyl-6-benzyloxy-7-methoxytetrahydroisoquinoline 261

A solution of 260 (6.281 g, 18.5 mmol) in ethanol (69 mL) was treatedwith potassium hydroxide (10.14 g, 181 mmol) in water (23 mL) and heatedat 120° C. for 88 h. A further aliquot of potassium hydroxide (10.12 g)was then added as a solution in water (23 mL) and heating continued at140° C. for another 80 h. The reaction mixture was cooled to roomtemperature and concentrated in vacuo. The formed precipitate wastreated with water (100 mL) and collected on a sinter funnel. The solidwas dissolved in dichloromethane (100 mL) and washed with water (50 mL)and brine (50 mL), dried (MgSO₄), filtered and concentrated in vacuo.The crude product (5.01 g) was dry-loaded onto SiO₂ (15 g) and purifiedby flash column chromatography (SiO₂: 80 g, ethyl acetate 100% and 0.5%triethylamine to ethyl acetate/methanol 80:20 and 0.5% triethylamine) toobtain the title compound (4.23 g, 76%) as beige solid. ¹H NMR (270 MHz,CDCl₃) δ 0.98 (3H, t, J 7.4, CH₂CH₃), 1.39-1.63 (2H, m, CH₂CH₃), 1.72(1H, s, br, NH), 2.34 (1H, dd, J 16.0, 10.2, one of ArCH₂CH), 2.63 (1H,dd, J 15.8, 3.8, one of ArCH₂CH), 2.65-2.78 (1H, m, ArCH₂CH), 3.82 (3H,s, OCH₃), 3.93 (1H, d, J 15.7, one of ArCH₂NH), 4.01 (1H, d, J 15.7, oneof ArCH₂NH), 5.09 (2H, s, OCH₂Ph), 6.53 (1H, s, CH), 6.58 (1H, s, CH),7.23-7.45 (5H, m, OCH₂C₆H₅). ¹³C NMR (67.5 MHz, CDCl₃) δ 10.4, 29.5,34.4, 48.3, 55.2, 56.0, 71.0, 109.3, 114.6, 126.6, 127.2, 127.7, 128.1,128.4, 137.2, 146.5, 147.8.

3-Ethyl-6-benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)tetrahydroisoquinoline262

A solution of 261 (297 mg, 1.0 mmol) in anhydrous DMF (3.0 mL), DIPEA(264 mg, 2.0 mmol) and 3,4,5-trimethoxybenzyl chloride (238 mg, 1.1mmol) was heated to 80° C. for 12 h, cooled to room temperature andpoured into water (50 mL) and ammonium chloride (saturated, 2 mL). Themixture was extracted with ethyl acetate (2×30 mL). The combined organiclayers were dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography using Flashmaster(SiO₂: 20 g, hexane 100% to hexane/ethyl acetate 50:50). The titlecompound was obtained as pale yellow oil (350 mg, 73%). ¹H NMR (270 MHz,CDCl₃) δ 0.97 (3H, t, J 7.0, CH₂CH₃), 1.43 (1H, sept, J 7.0, one ofCH₂CH₃), 1.67 (1H, sept, J 7.0, one of CH₂CH₃), 2.42-2.58 (1H, m, one ofArCH₂CH), 2.72-2.95 (2H, m, one of ArCH₂CH, CHN), 3.51-3.74 (4H, m,2×ArCH₂N), 3.80 (3H, s, OCH₃), 3.83 (6H, s, 2×OCH₃), 3.88 (3H, s, OCH₃),5.10 (2H, s, OCH₂Ph), 6.45-6.56 (1H, m, CH), 6.56-6.70 (3H, m, 3×CH),7.24-7.52 (5H, m, OCH₂C₆H₅).

3-Ethyl-6-benzyloxy-7-methoxy-2-(3-methoxybenzyl)-tetrahydroisoquinoline263

A solution of 261 (297 mg, 1.0 mmol) in anhydrous DMF (3.0 mL), DIPEA(263 mg, 2.0 mmol) and 3-methoxybenzyl bromide (222 mg, 1.1 mmol) washeated to 80° C. for 12 h, cooled to room temperature and poured intowater (50 mL) and ammonium chloride (saturated, 2 mL). The mixture wasextracted with ethyl acetate (2×30 mL). The combined organic layers weredried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash column chromatography using Flashmaster (SiO₂: 20 g,hexane 100% to hexane/ethyl acetate 70:30). The title compound wasobtained as pale yellow oil (323 mg, 77%). ¹H NMR (270 MHz, CDCl₃) δ1.02 (3H, t, J 7.4, CH₂CH₃), 1.46 (1H, sept, J 7.2, one of CH₂CH₃), 1.73(1H, sept, J 6.8, one of CH₂CH₃), 2.55 (1H, dd, J 16.2, 6.1, one ofArCH₂CH), 2.82 (1H, dd, J 16.2, 5.0, one of ArCH₂CH), 2.85-2.98 (1H, m,CHN), 3.61-3.77 (4H, m, 2×ArCH₂N), 3.84 (6H, s, 2×OCH₃), 5.16 (2H, s,OCH₂Ph), 6.52 (1H, s, CH), 6.67 (1H, s, CH), 6.81-6.87 (1H, m, CH),6.95-7.02 (2H, m, 2×CH), 7.23-7.52 (5H, m, OCH₂C₆H₅), 7.27 (1H, t, J6.9, CH).

3-Ethyl-6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)tetrahydroisoquinoline264

Pd/C (10%, 30.7 mg) was covered with THF (2.0 mL) and ethanol (2.0 mL)and stirred under an atmosphere of hydrogen (balloon pressure) for 15min at room temperature. Then 262 (334 mg, 0.7 mmol) was added as asolution in THF (4.0 mL). The reaction mixture was stirred for 18 h atroom temperature, then filtered through celite. The celite was washedwith ethyl acetate (4×5 mL) and the combined filtrates were concentratedin vacuo. The residue was recrystallised from ether/dichloromethane toobtain the title compound as yellow solid (253 mg, 93%). ¹H NMR (400MHz, CDCl₃) δ 0.98 (3H, t, J 7.4, CH₂CH₃), 1.41 (1H, sept, J 7.0, one ofCH₂CH₃), 1.68 (1H, sept, J 6.9, one of CH₂CH₃), 2.51 (1H, dd, J 16.4,5.9, one of ArCH₂CH), 2.75-2.84 (2H, m, one of ArCH₂CH, CHN), 3.51-3.75(4H, m, 2×ArCH₂N), 3.80 (3H, s, OCH₃), 3.83 (9H, s, 3×OCH₃), 6.44 (1H,s, CH), 6.60 (2H, s, 2×CH), 6.65 (1H, s, CH). ¹³C NMR (100 MHz, CDCl₃) δ11.1, 23.0, 29.4, 50.8, 55.2, 55.9, 56.0, 58.3, 60.9, 105.3, 108.8,114.6, 125.4, 126.7, 135.6, 136.5, 143.9, 144.9, 153.1. LC/MS (ES⁺)t_(r) 1.03 min; m/z 388.13 ((M+H)⁺, 100%); MeOH/H₂O 95:5 (1.0 mL/min),HPLC tr 2.58 min (>97%); CH₃CN/H₂O 90:10 (1.0 mL/min).

3-Ethyl-6-hydroxy-7-methoxy-2-(3-methoxybenzyl)-tetrahydroisoquinoline265

Pd/C (10%, 30.3 mg), THF (2.0 mL) and ethanol (2.0 mL) were reacted with263 (292, 0.7 mmol) in THF (4.0 mL) as described for the synthesis of264. The residue was purified by flash column chromatography usingFlashmaster (SiO₂: 5 g, hexane 100% to hexane/ethyl acetate 60:40). Thetitle compound was obtained as yellow oil (211 mg, 92%). ¹H NMR (400MHz, CDCl₃) δ 0.98 (3H, t, J 7.2, CH₂CH₃), 1.42 (1H, sept, J 7.1, one ofCH₂CH₃), 1.69 (1H, sept, J 6.8, one of CH₂CH₃), 2.52 (1H, dd, J 16.4,6.3, one of ArCH₂CH), 2.80 (1H, dd, J 16.4, 5.1, one of ArCH₂CH),2.86-2.90 (1H, m, CHN), 3.58-3.73 (4H, m, 2×ArCH₂N), 3.80 (6H, s,2×OCH₃), 6.42 (1H, s, CH), 6.64 (1H, s, CH), 6.79 (1H, dd, J 8.0, 2.2,CH), 6.92-6.98 (2H, m, 2×CH), 7.22 (1H, t, J 7.8, CH). ¹³C NMR (100 MHz,CDCl₃) δ 11.1, 23.0, 29.5, 50.9, 55.0, 55.1, 55.9, 58.5, 108.8, 112.3,114.1, 114.6, 121.1, 125.3, 126.7, 129.1, 141.5, 143.9, 144.9, 159.6.LC/MS (ES⁺) t_(r) 1.13 min; m/z 328.10 ((M+H)⁺, 100%); MeOH/H₂O 95:5(1.0 mL/min), HPLC tr 2.86 min (>99%); CH₃CN/H₂O 90:10 (1.0 mL/min).

3-Ethyl-6-O-sulfamoyl-7-methoxy-2-(3-methoxybenzyl)tetrahydroisoquinoline266

A solution of 265 (164 mg, 0.5 mmol) in anhydrous DMA (1.0 mL) wascooled to 0° C. then treated with sulfamoyl chloride (1.5 mmol) inanhydrous DMA (2.0 mL). The reaction mixture was stirred for 2 h at 0°C., then diluted with ethyl acetate (30 mL). The mixture was washed withNa₂CO₃ (half-saturated, 50 mL), dried (MgSO₄) and concentrated in vacuo.The residue was purified by flash column chromatography usingFlashmaster (SiO₂: 20 g, hexane 100% to hexane/ethyl acetate 50:50). Theresidue was dissolved in dichloromethane (5 mL) and ether (25 mL) andconcentrated in vacuo very quickly to obtain the title compound asyellow solid (106 mg, 52%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.93 (3H, t, J7.2, CH₂CH₃, 1.34 (1H, sept, J 7.0, one of CH₂CH₃), 1.63 (1H, sept, J6.8, one of CH₂CH₃), 2.47-2.58 (1H, m, one of ArCH₂CH), 2.74-2.88 (2H,m, one of ArCH₂CH, CHN), 3.51-3.68 (4H, m, 2×ArCH₂N), 3.70 (3H, s,OCH₃), 3.72 (3H, s, OCH₃), 6.78 (1H, s, CH), 6.78-6.83 (1H, m, CH),6.87-6.93 (2H, m, 2×CH), 7.03 (1H, s, CH), 7.23 (1H, t, J 8.0, CH), 7.85(2H, s, NH₂). ¹³C NMR (100 MHz, DMSO-d₆) δ 11.1, 22.3, 29.2, 50.6, 55.1,55.1, 56.0, 57.9, 111.4, 112.4, 114.0, 120.8, 123.5, 125.7, 129.5,133.1, 137.2, 141.5, 149.9, 159.5. LC/MS (ES⁻) t_(r) 1.19 min; m/z405.01 ((M+H)⁻, 100%); MeOH/H₂O 95:5 (1.0 mL/min), HPLC tr 2.09 min97.4%); CH₃CN/H₂O 90:10 (1.0 mL/min).

3-Ethyl-6-O-sulfamoyl-7-methoxy-2-(3,4,5-trimethoxybenzyl)tetrahydroisoquinoline267

A solution of 263 (194 mg, 0.5 mmol) in anhydrous DMA (1.0 mL) wascooled to 0° C. and treated with sulfamoyl chloride (1.5 mmol) inanhydrous DMA (2.0 mL) as described for the synthesis of 266. Theresidue was purified by flash column chromatography using Flashmaster(SiO₂: 20 g, hexane 100% to hexane/ethyl acetate 20:80). The residue wasdissolved in dichloromethane (30 mL) and concentrated in vacuo veryquickly to obtain the title compound as fluffy yellow solid (172 mg,73%). ¹H NMR (400 MHz, DMSO-d₆) δ 0.94 (3H, t, J 7.4, CH₂CH₃), 1.33 (1H,sept, J 7.0, one of CH₂CH₃), 1.62 (1H, sept, J 6.8, one of CH₂CH₃),2.46-2.54 (1H, m, one of ArCH₂CH), 2.76-2.87 (2H, m, one of ArCH₂CH,CHN), 3.51-3.66 (4H, m, 2×ArCH₂N), 3.63 (3H, s, OCH₃), 3.70 (3H, s,OCH₃), 3.73 (6H, s, 2×OCH₃), 6.64 (2H, s, CH), 6.81 (1H, s, CH), 7.03(1H, s, CH), 7.85 (2H, s, NH₂). ¹³C NMR (100 MHz, DMSO-d₆) δ 11.2, 22.3,29.0, 50.5, 55.3, 55.9, 56.0, 57.6, 60.2, 105.3, 111.4, 123.3, 125.7,133.2, 135.5, 136.3, 137.3, 149.9, 153.0. LC/MS (ES⁺) t_(r) 1.13 min;m/z 467.11 ((M+H)⁺, 100%); MeOH/H₂O 95:5 (1.0 mL/min), HPLC tr 1.86 min(97.6%); CH₃CN/H₂O 90:10 (1.0 mL/min).

N-Acyl-3-methoxyphenethylamine 268

To a 0° C. solution of 3-methoxyphenethylamine (10 g, 66 mmol) andtriethylamine (11.03 mL, 79.4 mmol) in dichloromethane (100 mL) wasadded acetic anhydride in a dropwise manner. The reaction mixture wasthen allowed to come to room temperature overnight and then washed withwater (3×100 mL), brine (100 mL), dried and evaporated to give thedesired product as a pale yellow oil (10.97 g, 93.7%) which showed ¹HNMR δ 1.90 (3H, s, Ac), 2.77 (2H, t, J 6.9, ArCH₂), 3.48 (2H, m, NCH₂),3.77 (3H, s, OMe), 5.62 (1H, br, NH), 6.68-6.82 (3H, m) and 7.21 (1H, t,J 8.0); ¹³C δ 22.3, 33.6, 40.5, 55.1, 111.7, 114.4, 121.0, 140.4, 159.7,170.0; HRMS [ES+ve] C₁₁H₁₅NO₂ found 194.1172 calculated 194.1176 [M⁺+H].

6-Methoxy-2-acyl-tetrahydroisoquinoline 269

A mixture of N-acyl-3-methoxyphenethylamine (10.9 g, 61.5 mmol),paraformaldehyde (5 g) and tosic acid (0.5 g) in toluene (200 mL) wasrefluxed for three days with extra aliquots of paraformaldehyde (2 g)being added after 24 and 48 h. The reaction was then cooled to rt, theorganic layers washed with water, brine, dried and evaporated to givethe desired tetrahydroisoquinoline as a pale yellow oil (9.4 g, 74.5%)which appears to exist as two conformers by NMR ¹H NMR δ 2.14 & 2.15(3H, 2×s), 2.80 & 2.86 (2H, 2×t, J 6.0), 3.63 & 3.80 (2H, 2×t, J 6.0),3.77 (3H, 2×s), 4.5 &4.63 (2H, 2×s) and 6.64-7.08 (3H, m); HRMS [ES+ve]C₁₂H₁₅NO₂ found 206.1175 calculated 206.1176 [M⁺+H].

7-Acyl-6-methoxy-2-acyl-tetrahydroisoquinoline 270

To an ice cold suspension of aluminium trichloride (3.20 g, 2.4 mmol) indichloromethane (20 mL) was added acetyl chloride (1.59 mL, 22.5 mmol)and then, after 0.5 h stirring at rt,6-methoxy-2-acyl-tetrahydroisoquinoline (1.91 g, 9.3 mmol). The reactionturned red on addition of the isoquinolone and turned an intensered/brown colour on further stirring. After 2.5 h the reaction wasquenched by pouring onto ice water (50 mL), the mixture was then treatedwith dichloromethane (50 mL) and the organic layer separated, washedwith water, then brine, dried and evaporated to give an orange oil.Chromatography (eluant 0-10% methanol in ethyl acetate afforded thedesired product as a beige solid (1.7 g, 73.9%) which was contaminatedby ca 10% of the corresponding 6-hydroxy compound and showed ¹H NMR δ2.14 (3H, s), 2.57 & 2.59 (3H, 2×s), 2.84 & 2.89 (2H, 2×t, J 5.8), 3.65& 3.79 (2H, 2×t, J 5.8), 3.87 & 3.88 (3H, 2×s, OMe), 6.70 & 6.72 (1H,2×s) and 7.51 (1H, s).

7-Acyl-6-hydroxy-2-acyl-tetrahydroisoquinoline 271

To an ice cold suspension of aluminium trichloride (9.17 g, 68.7 mmol)in dichloromethane (33 mL) was added trimethylamine hydrochloride (3.28g, 34.3 mmol), the mixture was then stirred for 1 h during which timemost of the AlCl₃ dissolved. A solution of the methyl ether (1.70 g,6.87 mmol) in DCM (14 mL) was then introduced in a dropwise manner andthen the reaction was heated to reflux for 2 h. The reaction was thencooled to rt and then cautiously poured onto ice (100 g, strongexotherm), before adding an aliquot of DCM (20 ml). The organic layerwas separated, washed with water (2×20 mL), 2M HCl (20 mL), water (20mL) then brine, dried and evaporated to give a pale brown oil whichsolidifies to give a beige solid on standing. As with previous compoundsin the series the ¹H NMR shows two conformers δ 2.13,& 2.15 (3H, 2×s),2.56 & 2.57 (3H, 2×s), 2.79 & 2.86 (2H, 2×t, J 6.0), 3.62 & 3.74 (2H,2×t, J 6.0), 4.54 & 4.63 (2H, 2×s), 6.72 & 6.73 (1H, 2×s), 7.44 & 7.46(1H, 2×s) and 12.1 (1H, 2×s).

7-Acyl-6-benzyloxy-2-acyl tetrahydroisoquinoline 272

A solution of the 7-acyl-6-hydroxy-2-acyl-tetrahydroisoquinoline (4.5 g,19.3 mmol) in DMF (75 mL) was treated with potassium C(Ar)bonate (6.67g, 48.3 mmol) and benzyl bromide (2.41 mL, 20.3 mmol) then heated to 90°C. for 1 h. The reaction was cooled and treated with water (100 mL) andethyl acetate (100 mL), the organic layer separated, washed with water(5×100 mL), brine (100 mL), dried and evaporate to give a brown oil.Column chromatography (0-10% methanol in ethyl acetate) gave a beigesolid which showed ¹H NMR δ 2.14 (3H, s), 2.54 & 2.56 (3H, 2×s),2.78-2.90 (2H, m), 3.62 & 3.77 (2H, 2×t, J 5.8), 4.54 & 4.65 (2H, 2×s),5.11 & 5.12 (2H, 2×s), 6.77 & 6.79 (1H, 2×s), 7.28-7.44 (5H, m) and 7.52(1H, s).

7-O-Acyl-6-benzyloxy-2-acyl tetrahydroisoquinoline 273

A solution of 7-acyl-6-benzyloxy-2-acyl tetrahydroisoquinoline (4.4 g,13.6 mmol) in dichloromethane (140 mL) was treated with mCPBA (4 eq) andthen stirred at room temperature overnight. The solvent was then removedby evaporation and the residues dissolved in ethyl acetate (150 mL) andstirred with aqueous potassium C(Ar)bonate (50 mL, 10%) for 0.25 h. Theorganic layer was then separated, washed with aqueous potassiumC(Ar)bonate (100 mL, 10%), water (150 mL), brine (100 ml), dried andevaporated. Column chromatography (ethyl acetate) gave the desiredacetate as a pale yellow oil (2.3 g, 49.8%) which showed ¹H NMR δ 2.14(3H, s), 2.25 & 2.26 (3H, 2×s), 2.76 & 2.81 (2H, 2×t, J 6.0), 3.62 &3.77 (2H, 2×t, J 6.0), 4.51 & 4.62 (2H, 2×s), 5.04 & 5.05 (2H, 2×s),6.73-6.83 (2H, m) and 7.28-7.43 (5H, m).

7-Hydroxy-6-benzyloxy-2-acyl tetrahydroisoquinoline 274

A solution of 7-O-acyl-6-benzyloxy-2-acyl tetrahydroisoquinoline (2.0 g,5.9 mmol) in acetone (60 mL) was treated with sodium hydroxide (15 mL,30 mmol). After 0.75 h HCl (2M) was added to neutralise the solution,acetone was removed by evaporation and the residues taken up in ethylacetate, washed with water, brine, dried and evaporated to give thedesired phenol which was used without further purification.

7-Ethoxy-6-benzyloxy-2-acyl tetrahydroisoquinoline 275

7-Hydroxy-6-benzyloxy-2-acyl tetrahydroisoquinoline (5.9 mmol),potassium C(Ar)bonate (2.76 g, 20 mmol), tetrabutyl ammonium iodide (50mg) and ethyl iodide (0.97 mL, 12 mmol) were treated with DMF (30 mL)and stirred overnight. Water and ethyl acetate (100 mL each) were thenintroduced and the resultant organic layer was separated, washed withwater (3×), brine, dried and evaporated to give the desired ethoxycompound as an amber oil which was used without further purification.

7-Ethoxy-6-benzyloxytetrahydroisoquinoline acetate 276

7-Ethoxy-6-benzyloxy-2-acyl tetrahydroisoquinoline (1.5 g) was refluxedovernight with ethanol (60 mL) and sodium hydroxide (15 mL, 10%). Thesolution was neutralised by adding acetic acid, the solvent removed byevaporation and the residue taken up in chloroform. The organic extractwas washed with water, brine, dried and evaporated to give the desiredtetrahydroisoquinoline as its acetate salt which showed ¹H NMR δ 1.39(3H, t, J 7.0), 1.88 (3H, s), 2.63 (2H, t, J 7.0), 3.07 (2H, t, J 6.0),3.43 (2H, app d, J 0.5), 3.90 (2H, s), 4.04 (2H, q, J 7.0), 5.08 (2H,s), 6.52 (1H, s), 6.61 (1H, s) and 7.26-7.47 (5H, m).

7-Ethoxy-6-benzyloxy-2-(3,4,5-trimethoxybenzyl)-tetrahydroisoquinoline277

A solution of 7-ethoxy-6-benzyloxytetrahydroisoquinoline acetate (293mg, 0.86 mmol), Hunig's base (0.325 mL, 1.96 mmol) and3,4,5-trimethoxybenzyl chloride (247 mg, 1.14 mmol) in DMF (8 mL) wereheated to 80° C. overnight. Water and ethyl acetate (50 mL each) werethen added to the cooled solution, the organic layer separated andwashed with water (5×), brine, dried and evaporated. The desired productwas isolated by column chromatography (3:2 hexane/ethyl acetate) to givethe product as a clear colourless oil (340 mg, 85%) which showed ¹H NMRδ 1.41 (3H, t, J 7.0), 2.63-2.80 (4H, m), 3.54 (2H, s), 3.58 (2H, s),3.84 (3H, s), 3.84 (6H, s), 4.03 (2H, q, J 7.0), 5.09 (2H, s), 6.54 (1H,s), 6.61 (2H, s), 6.65 (1H, s) and 7.26-7.44 (5H, m). m/z HRMS [ES+]found 464.2413, C₂₈H₃₄NO₅ (M₊+H) requires 464.2437.

7-Ethoxy-6-hydroxy-2-(3,4,5-trimethoxybenzyl)-tetrahydroisoquinoline 278

7-Ethoxy-6-benzyloxy-2-(3,4,5-trimethoxybenzyl)-tetrahydroisoquinolineacetate (307 mg, 0.66 mmol) was dissolved in ethanol and ethyl acetate(5 mL each), degassed, treated with 10% Pd/C (50 mg) then placed underan atmosphere of hydrogen. After 0.5 h no starting material was evidentby TLC and the reaction was filtered through celite and evaporated. Theresultant oil was precipitated from ethyl acetate/hexane to give ayellow powder (240 mg, 97%). ¹H NMR δ 1.39 (3H, t, J 7.0), 2.68 (2H, t,J 5.7), 2.75 (2H, t, J 5.7), 3.52 (2H, s), 3.58 (2H, s), 3.83 (3H, s),3.84 (6H, s), 4.01 (2H, q, J 7.0), 5.50 (1H, br), 6.46 (1H, s), 6.61(2H, s) and 6.67 (1H, s).

7-Ethoxy-6-O-sulfamoyl-2-(3,4,5-trimethoxybenzyl)-tetrahydroisoquinoline279

7-Ethoxy-6-hydroxy-2-(3,4,5-trimethoxybenzyl)-tetrahydroisoquinoline(140 mg, 0.375 mmol) was reacted with a solution of sulfamoyl chloride(1.5 mmol) in dimethyl acetamide (1.5 mL). After stirring overnightethyl acetate (50 mL) and water (25 mL) were added, the aqueous basifiedby addition of sodium biC(Ar)bonate, the organic layer separated, washedwith water (5×), brine, dried and evaporated. The desired sulfamate waspurified by column chromatography (3:2 chloroform/acetone) to give apale yellow oil (118 mg, 70%). Precipitation from ether/hexane then gavea yellow powder 74 mg. ¹H NMR δ 1.40 (3H, t, J 6.9), 2.71 (2H, t, J5.5), 2.82 (2H, t, J 5.5), 3.55 (2H, s), 3.59 (2H, s), 3.83 (3H, s),3.84 (6H, s), 4.04 (2H, q, J 6.9), 5.02 (2H, br), 6.60 (1H, s), 6.60(2H, s) and 7.06 (1H, s); m/z [ES−] 450.99 (100%, M⁺−H); HRMS [ES+]found 453.1690, C₂₁H₂₉H₂O₇S (M⁺+H) requires 452.1696.

7-Ethyl-6-hydroxy-2-acyl-tetrahydroisoquinoline 280

A stirred solution of 7-acyl-6-hydroxy-2-acyl-tetrahydroisoquinoline(8.2 g, 35.2 mmol) in trifluoroacetic acid (27.1 mL, 352 mmol) wastreated with triethylsilane (12.36 mL, 77.4 mmol) in a dropwise mannerat rt. After 14 h the solvent was evaporated, methanol was added andthen mixture re-evaporated to remove any residual TFA and the residueloaded onto silica gel. Column chromatography (2:1 chloroform/ethylacetate) gave the desired product as a brown oil (5.4 g, 70%) whichshowed ¹H NMR δ 1.19 & 1.20 (3H, 2×t, J 7.4), 2.22 & 2.24 (3H, 2×s),2.58 & 2.60 (2H, 2×q, J 7.4), 2.73 & 2.77 (2H, 2×t, J 6.1), 3.64 & 3.78(2H, 2×t, J 6.1), 4.54 & 4.65 (2H, 2×s), 6.60 (1H, 2×s), 6.85 &6.86 (1H,2×s) and 9.00-10.50 (1H, br).

7-Ethyl-6-O-benzyl-2-acyl-tetrahydroisoquinoline 281

A solution of 7-ethyl-6-hydroxy-2-acyl-tetrahydroisoquinoline (3.1 g,14.1 mmol) in DMF (70 mL) was treated with sodium hydride (800 mg, 20mmol) and then, after 15 minutes, benzyl bromide (2.38 mL, 20 mmol).After 72 h the reaction was quenched by adding water (100 mL) followedby ethyl acetate (100 mL). The organic layer was separated and washedrepeatedly with water, then brine, dried and evaporated. The crudeproduct was purified by column chromatography (ethyl acetate with 4drops Et₃N per 100 mL to basify) to give the desired benzylated productas a pale yellow oil (2.2 g, 51%) which showed ¹H NMR δ 1.20 & 1.21 (3H,2×t, J 7.4), 2.16 & 2.17 (3H, 2×s), 2.66 & 2.67 (2H, 2×q, J 7.4), 2.78 &2.83 (2H, 2×t, J 5.9), 3.64 & 3.79 (2H, 2×t, J 5.9), 4.54 & 4.65 (2H,2×s), 5.06 & 5.09 (2H, 2×s), 6.65 & 6.68 (1H, 2×s), 6.90 & 6.94 (1H,2×s) and 7.29-7.45 (5H, m).

7-Ethyl-6-O-benzyl tetrahydroisoquinoline 282

7-Ethyl-6-O-benzyl-2-acyl-tetrahydroisoquinoline (2.2 g, 7.1 mmol) wasrefluxed with ethanol (60 mL) and sodium hydroxide (2M, 15 mL)overnight. The solvent was then removed by evaporation and the residueextracted into chloroform (100 mL), the extract washed with water (2×50mL), brine (50 mL), dried and evaporated to give a pale yellow oil (1.9g, quant.) which was used without purification. ¹H NMR δ 1.19 (3H, t, J7.4), 1.74 (1H, br), 2.64 (2H, q, J 7.4), 2.73 (2H, t, J 5.8), 3.10 (2H,t, J 5.8), 3.94 (2H, s), 5.04 (2H, s), 6.61 (1H, s), 6.81 (1H, s) and7.28-7.47 (5H, m).

7-Ethyl-6-O-benzyl-2-(3-methoxybenzyl)tetrahydroisoquinoline 283

A solution of 7-ethyl-6-O-benzyl tetrahydroisoquinoline (358 mg, 1.34mmol), dimethylformamide (8 mL), Hunig's base (443 μL, 2.67 mmol) and3-methoxybenzyl chloride (214 μL, 1.47 mmol) were stirred overnight at80° C. Ethyl acetate (40 mL) was added to the cooled reaction mixtureand the organic layer was washed with water (4×40 mL), brine, dried andevaporated to give a brown oil. Column chromatography (3:1 hexane/ethylacetate with 4 drops Et₃N per 100 mL to basify) gave the desired productas a pale yellow oil (300 mg, 58%) which showed ¹H NMR δ 1.18 (3H, t, J7.4), 2.63 (2H, q, J 7.4), 2.71 (2H, t, J 5.8), 2.84 (2H, t, J 5.8),3.56 (2H, s), 3.65 (2H, s), 3.81 (3H, s), 5.04 (2H, s), 6.64 (1H, s),6.78-6.84 (2H, m), 6.94-7.01 (2H, m) and 7.20-7.47 (6H, m).

7-Ethyl-6-hydroxy-2-(3-methoxybenzyl)tetrahydroisoquinoline 284

A solution of7-ethyl-6-O-benzyl-2-(3-methoxybenzyl)tetrahydroisoquinoline (260 mg,0.67 mmol) in ethanol (5 mL) and ethyl acetate (5 mL) was degassed byboiling, treated with 5% Pd/C (50 mg) and then placed under anatmosphere of hydrogen at room temperature for 5 h. The mixture was thenfiltered through celite and the solvent evaporated. Columnchromatography (3:2 Hexane/ethyl acetate with 4 drops Et₃N per 100 mL tobasify) delivered then desired product (140 mg, 70%) as an off whitesolid which showed ¹H NMR δ 1.16 (3H, t, J 7.4), 2.53 (2H, q, J 7.4),2.68-2.78 (4H, m), 3.53 (2H, s), 3.64 (2H, s), 3.78 (3H, s), 5.10-5.30(2H, br), 6.37 (1H, s), 6.73 (1H, s), 6.81 (1H, m), 6.95-6.98 (2H, m)and 7.23 (1H, dd, J 7.9 & 7.9)

7-Ethyl-6-O-sulfamoyl-2-(3-methoxybenzyl)tetrahydroisoquinoline 285

7-Ethyl-6-hydroxy-2-(3-methoxybenzyl)tetrahydroisoquinoline (98 mg, 0.33mmol) was treated with a solution of sulfamoyl chloride (1 mmol) in DMA(1.5 mL). After overnight stirring the reaction was worked up bydiluting with ethyl acetate (30 mL) and saturated sodium biC(Ar)bonatesolution (15 mL), the organic layer was separated and washed with water(5×), then brine, dried and evaporated to give the desired sulfamate (90mg, 72%) as a pale yellow oil which showed ¹H NMR δ 1.14 (3H, t, J 7.4),2.63 (2H, q, J 7.4), 2.74 (2H, t, J 5.8), 2.85 (2H, t, J 5.8), 3.60 (2H,s), 3.68 (2H, s), 3.79 (3H, s), 4.70-5.20 (2H, br), 6.78-6.84 (1H, m),6.87 (1H, s), 6.94-6.98 (2H, m) 7.09 (1H, s) and 7.20-7.26 (1H, m).

Synthesis of1-(benzyl)-6-benzyloxy-7-methoxy-3,4-dihydro-1H-quinolin-2-ones

General Method:

NaH (120 mg, 3 mmol) was added portion wise under nitrogen to a stirredsolution of 6-(benzyloxy)-7-methoxy-3,4-dihydroquinolin-2(1H)-one (425mg, 1.5 mmol) in DMF (5 mL). The mixture was stirred for 30 minutesbefore the appropriate benzyl bromide or benzyl chloride (1.65 mmol) wasadded and the mixture stirred for 6 hours at rt. After addition ofwater, the organics were extracted with ethyl acetate (2×50 mL). Theorganic layer was washed with water, brine, dried (MgSO₄), filtered andthe solvent evaporated under vacuum. The residual solid was purified byflash chromatography.

6-(Benzyloxy)-7-methoxy-1-(2-methoxybenzyl)-3,4-dihydro-1H-quinolin-2-one286

Colorless oil, 430 mg (71%), R_(f): 0.66 (hexane/ethyl acetate 1:1), ¹HNMR (270 MHz, CDCl₃) δ 2.68-2.86 (4H, m, 2×CH₂), 3.65 (3H, s, CH₃O),3.88 (3H, s, CH₃O), 5.06 (2H, s, CH₂), 5.17 (2H, s, CH₂), 6.50 (1H, s,ArH), 6.69 (1H, s, ArH), 6.81-6.89 (2H, m, ArH), 7.01 (1H, dd, J 7.4 and1.4 Hz, ArH), 7.16-7.43 (6H, m, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ 25.0(CH₂), 32.2 (CH₂), 40.6 (CH₂), 55.5 (CH₃O), 56.2 (CH₃O), 71.7 (CH₂),101.9 (CH), 110.3 (CH), 114.5 (CH), 118.0 (C), 121.0 (CH), 125.0 (C),127.4 (2×CH), 128.0 (CH), 128.2 (CH), 128.6 (2×CH), 133.9 (C), 137.3(C), 143.6 (C), 148.7 (C), 156.6 (C), 170.5 (CO).

6-(Benzyloxy)-7-methoxy-1-(3-methoxybenzyl)-3,4-dihydro-1H-quinolin-2-one287

Yellow oil, 350 mg (58%), R_(f): 0.63 (hexane/ethyl acetate 1:1), ¹H NMR(270 MHz, CDCl₃) δ 2.67-2.88 (4H, m, 2×CH₂), 3.64 (3H, s, CH₃O), 3.74(3H, s, CH₃O), 5.06 (2H, s, CH₂), 5.11 (2H, s, CH₂), 6.50 (1H, s, ArH),6.69 (1H, s, ArH), 6.71-6.84 (3H, m, ArH), 7.18-7.42 (6H, m, ArH). HPLCt_(r)=5.12 min (71.3%) and 6.10 (28.7%). (CH₃CN/H₂O 70/30); LC/MS (ES+)t_(r)=2.52 min m/z 426.17 ((M+Na)⁺, 100%), 404.19 (M+H)⁺ and tr=3.21 minm/z 438.2 ((M+Na)⁺, 100%), 416.22 (M+H)⁺; MeOH/H₂O 80/20

6-(Benzyloxy)-7-methoxy-1-(4-methoxybenzyl)-3,4-dihydro-1H-quinolin-2-one288

White solid, 390 mg (64%), R_(f): 0.71 (hexane/ethyl acetate 3:1), ¹HNMR (270 MHz, CDCl₃) δ 2.66-2.84 (4H, m, 2×CH₂), 3.66 (3H, s, CH₃O),3.78 (3H, s, CH₃O), 5.06 (2H, s, CH₂), 5.07 (2H, s, CH₂), 6.52 (1H, s,ArH), 6.67 (1H, s, ArH), 6.82 (2H, d, J 8.8 Hz, ArH), 7.15 (2H, d, J 8.8Hz, ArH), 7.26-7.44 (5H, m, ArH); HPLC t_(r)=4.97 min (84.5%).(CH₃CN/H₂O 90:10); LC/MS (ES+) t_(r)=6.38 min m/z 426.24 (M+Na)⁺, 404.19(M+H)⁺; MeOH/H₂O 70/30

6-(Benzyloxy)-7-methoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydro-1H-quinolin-2-one289

White solid, 300 mg (43%), mp 129-130° C., R_(f): 0.28 (hexane/ethylacetate 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.67-2.74 (2H, m, CH₂),2.79-2.85 (2H, m, CH₂), 3.68 (3H, s, CH₃O), 3.78 (6H, s, 2×CH₃O), 3.80(3H, s, CH₃O), 5.05 (2H, s, CH₂), 5.07 (2H, s, CH₂), 6.45 (2H, s, ArH),6.54 (1H, s, ArH), 6.70 (1H, s, ArH), 7.26-7.42 (5H, m, Ph); ¹³C NMR(100 MHz, CDCl₃) δ 25.0 (CH₂), 32.2 (CH₂), 46.7 (CH₂), 56.1 (2×CH₃O),56.3 (CH₃O), 60.8 (CH₃O), 71.6 (CH₂), 101.9 (CH), 103.5 (2×CH), 114.4(CH), 118.1 (C), 127.3 (2×CH), 127.9 (CH), 128.5 (2×CH), 128.6 (2×CH),133.2 (C), 133.9 (C), 137.0 (C), 143.7 (C), 148.7 (C), 153.5 (C), 170.4(CO). LC/MS (ES+) t_(r)=0.99 min m/z 486.13 (M+Na)⁺, 464.15 (M+H)⁺;MeOH/H₂O 95/5 HPLC t_(r)=3.91 min (98.8%). (CH₃CN/H₂O 70:30).

Synthesis of1-(benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-quinolin-2-ones

General Method:

A solution of 1-benzyl-6-(benzyloxy)-3,4-dihydro-1H-quinolin-2-one (1mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C (40mg) and stirred under an atmosphere of hydrogen. The reaction wasmonitored by TLC. Upon completion, the resultant suspension was filteredthrough celite, washed with ethyl acetate and then evaporated underreduced pressure. The crude mixture was purified by flash chromatography(hexane/ethyl acetate) and the resulting solid stirred in diethyl ether.

6-Hydroxy-7-methoxy-1-(3-methoxybenzyl)-3,4-dihydro-1H-quinolin-2-one290

White powder, 240 mg (77%), mp 177-178° C., R_(f): 0.34 (hexane/ethylacetate 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68-2.75 (2H, m, CH₂),2.82-2.88 (2H, m, CH₂), 3.64 (3H, s, CH₃O), 3.88 (3H, s, CH₃O), 5.14(2H, s, CH₂), 5.35 (1H, s, OH), 6.44 (1H, s, ArH), 6.70 (1H, s, ArH),6.81-6.88 (2H, m, ArH), 6.98-7.02 (1H, m, ArH), 7.15-7.22 (1H, m, ArH);¹³C NMR (100 MHz, CDCl₃) δ 24.9 (CH₂), 32.2 (CH₂), 40.5 (CH₂), 55.4(CH₃O), 55.9 (CH₃O) 100.3 (CH), 110.1 (CH), 113.8 (CH), 118.9 (C), 120.9(CH), 125.0 (C), 127.3 (CH), 128.1 (CH), 132.6 (C), 140.8 (C), 145.2(C), 156.5 (C), 170.5 (CO). LC/MS (ES−) t_(r)=0.92 min m/z 312.17(M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=2.39 min (100.0%). (acetonitrile/water70/30)

6-Hydroxy-7-methoxy-1-(3-methoxybenzyl)-3,4-dihydro-1H-quinolin-2-one291

White powder, 80 mg (25%), mp 137-138° C., R_(f): 0.32 (hexane/ethylacetate 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68-2.75 (2H, m, CH₂),2.81-2.88 (2H, m, CH₂), 3.63 (3H, s, CH₃O), 3.74 (3H, s, CH₃O), 5.10(2H, s, CH₂), 5.39 (1H, s, OH), 6.43 (1H, s, ArH), 6.70 (1H, s, ArH),6.74-6.76 (2H, m, ArH), 6.81 (1H, d, J 7.7 Hz, ArH); ¹³C NMR (67.5 MHz,CDCl₃) δ 25.0 (CH₂), 32.3 (CH₂), 46.5 (CH₂), 55.2 (CH₃O), 56.0 (CH₃O)100.6 (CH), 112.4 (2×CH), 114.0 (CH), 118.9 (CH), 119.1 (C), 129.9 (CH),132.7 (C), 139.2 (C), 141.1 (C), 145.3 (C), 160.1 (C), 170.5 (CO). LC/MS(ES−) t_(r)=0.93 min m/z 312.10 (M−H)⁻; MeOH/H₂O 95/5 HPLC t_(r)=2.31min (100.0%). (acetonitrile/water 70/30)

6-Hydroxy-7-methoxy-1-(4-methoxybenzyl)-3,4-dihydro-1H-quinolin-2-one292

White powder, 125 mg (40%), mp 168-169° C., R_(f): 0.30 (hexane/ethylacetate 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.68-2.74 (2H, m, CH₂),2.80-2.86 (2H, m, CH₂), 3.66 (3H, s, CH₃O), 3.76 (3H, s, CH₃O), 5.07(2H, s, CH₂), 5.34 (1H, br, OH), 6.46 (1H, s, ArH), 6.70 (1H, s, ArH),6.83 (2H, d, J 8.5 Hz, ArH), 7.15 (2H, d, J 8.5 Hz, ArH); ¹³C NMR (67.5MHz, CDCl₃) δ 25.0 (CH₂), 32.3 (CH₂), 45.9 (CH₂), 55.4 (CH₃O), 56.0(CH₃O) 100.5 (CH), 114.0 (CH), 114.3 (2×CH), 119.2 (C), 127.9 (2×CH),129.5 (C), 132.8 (C), 141.0 (C), 145.2 (C), 158.7 (C), 170.5 (CO). LC/MS(ES−) t_(r)=0.90 min m/z 312.10 (M−H)⁻; MeOH/H₂O 95/5 HPLC t_(r)=2.28min (99.0%). (acetonitrile/water 70/30)

6-Hydroxy-7-methoxy-1-(3,4,5-trimethoxybenzyl)-3,4-dihydro-1H-quinolin-2-one293

White powder, 300 mg (80%), mp 157-158° C., R_(f): 0.53 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 2.68-2.75 (2H, m, CH₂), 2.81-2.87 (2H, m,CH₂), 3.67 (3H, s, CH₃O), 3.78 (6H, s, 2×CH₃O), 3.79 (3H, s, CH₃O), 5.05(2H, s, CH₂), 5.36 (1H, s, OH), 6.44 (1H, s, ArH), 6.48 (2H, s, ArH),6.72 (1H, s, ArH); ¹³C NMR (100 MHz, CDCl₃) δ 25.0 (CH₂), 32.2 (CH₂),46.8 (CH₂), 56.0 (CH₃O), 56.1 (2×CH₃O), 60.8 (CH₃O) 100.4 (CH), 103.4(2×CH), 113.9 (CH), 119.1 (C), 132.8 (C), 133.3 (C), 137.0 (C), 141.1(C), 145.2 (C), 153.6 (C), 170.4 (CO). LC/MS (ES−) t_(r)=0.86 min m/z372.13 (M−H)⁻; MeOH/H₂O 95/5 HPLC t_(r)=1.57 min (99.7%).(acetonitrile/water 90/10)

Synthesis of1-benzyl-7-methoxy-6-O-sulfamoyl-3,4-dihydro-1H-quinolin-2-ones

General Method:

A solution of1-(benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-1H-quinolin-2-ones (0.2 mmol)and sulfamoyl chloride (0.4 mmol) in DMA (1 mL) was stirred at rt undernitrogen for 24 hours. After addition of water (5 mL) the organics wereextracted into ethyl acetate (2×50 mL), the organic layers washed withwater and brine, then dried (MgSO₄) and evaporated. The crude productwas purified by flash chromatography (hexane/ethyl acetate or DCM/ethylacetate) and the resulting solid stirred in diethyl ether, filtered anddried under vacuum.

7-methoxy-1-(2-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-1H-quinolin-2-one294

White powder, 60 mg (76%), mp 175-176° C., R_(f): 0.68 (DCM/EtOAc 1:1),¹H NMR (270 MHz, DMSO-d6) δ 2.62-2.670 (2H, m, CH₂), 2.84-2.90 (2H, m,CH₂), 3.59 (3H, s, CH₃O), 3.87 (3H, s, CH₃O), 5.09 (2H, s, CH₂), 6.58(1H, s, ArH), 6.85 (1H, t, J 7.4 Hz, ArH), 6.96 (1H, dd, J 7.4 and 1.4Hz, ArH), 7.03 (1H, d, J 8.4 Hz, ArH), 7.15 (1H, s, ArH), 7.24 (1H, dt,J 8.4 and 1.4 Hz, ArH), 7.86 (2H, br, NH₂); ¹³C NMR (67.5 MHz, DMSO-d6)δ 23.8 (CH₂), 31.4 (CH₂), 39.9 (CH₂), 55.5 (CH₃O), 55.9 (CH₃O) 101.5(CH), 110.8 (CH), 117.9 (C), 120.6 (CH), 122.6 (CH), 124.4 (C), 127.0(CH), 128.4 (CH), 133.4 (C), 138.1 (C), 150.6 (C), 156.5 (C), 169.7(CO). LC/MS (ES−) t_(r)=0.87 min m/z 390.96 (M−H)⁻; MeOH/H₂O 95/5; HPLCt_(r)=2.29 min (100.0%). (acetonitrile/water 70/30)

7-methoxy-1-(3-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-1H-quinolin-2-one295

White powder, 48 mg (62%), mp 108-110° C., R_(f): 0.70 (DCM/EtOAc 1:1),¹H NMR (270 MHz, CDCl₃) δ 2.71-2.79 (2H, m, CH₂), 2.85-2.93 (2H, m,CH₂), 3.63 (3H, s, CH₃O), 3.75 (3H, s, CH₃O), 4.99 (2H, s, CH₂), 5.11(2H, s, NH₂), 6.53 (1H, s, ArH), 6.74-6.81 (3H, m, ArH), 7.11 (1H, s,ArH), 7.23 (1H, t, J 8.0 Hz, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ 24.5(CH₂), 31.7 (CH₂), 46.5 (CH₂), 55.2 (CH₃O), 56.3 (CH₃O) 101.9 (CH),112.3 (CH), 112.4 (CH), 118.7 (CH), 119.0 (C), 123.4 (CH), 130.0 (CH),133.6 (C), 138.5 (C), 139.5 (C), 150.3 (C), 160.1 (C), 170.4 (CO). LC/MS(ES−) t_(r)=0.87 min m/z 390.96 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=2.29min (100.0%). (acetonitrile/water 70/30)

7-methoxy-1-(4-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-1H-quinolin-2-one296

White powder, 61 mg (78%), mp 179-180° C., R_(f): 0.68 (DCM/EtOAc 1:1),¹H NMR (270 MHz, DMSO-d6) δ 2.61-2.68 (2H, m, CH₂), 2.80-2.86 (2H, m,CH₂), 3.65 (3H, s, CH₃O), 3.70 (3H, s, CH₃O), 5.13 (2H, s, CH₂), 6.75(1H, s, ArH), 6.87 (2H, d, J 8.8 Hz, ArH), 7.12 (1H, s, ArH), 7.23 (2H,d, J 8.8 Hz, ArH), 7.85 (2H, br, NH₂); ¹³C NMR (67.5 MHz, DMSO-d6) δ23.8 (CH₂), 31.4 (CH₂), 43.6 (CH₂), 55.0 (CH₃O), 56.1 (CH₃O) 102.2 (CH),114.0 (2×CH), 118.1 (CH), 122.5 (CH), 128.3 (2×CH), 129.3 (C), 133.4(C), 137.9 (C), 150.5 (C), 158.3 (C), 169.7 (CO). LC/MS (ES−) t_(r)=0.85min m/z 391.15 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.83 min (99.5%).(acetonitrile/water 70/30)

7-methoxy-6-O-sulfamoyl-1-(3,4,5-trimethoxybenzyl)-3,4-dihydro-1H-quinolin-2-one297

White powder, 66 mg (73%), mp 154-155° C., R_(f): 0.37 (ethyl acetate),¹H NMR (270 MHz, DMSO-d6) δ 2.65-2.70 (2H, m, CH₂), 2.82-2.88 (2H, m,CH₂), 3.60 (3H, s, CH₃O), 3.69 (3H, s, CH₃O), 3.71 (6H, s, 2×CH₃O), 5.12(2H, s, CH₂), 6.65 (2H, s, ArH), 6.82 (1H, s, ArH), 7.13 (1H, s, ArH),7.85 (2H, br, NH₂); ¹³C NMR (67.5 MHz, DMSO-d6) δ 24.3 (CH₂), 31.9(CH₂), 45.0 (CH₂), 56.3 (2×CH₃O), 56.6 (CH₃O), 60.5 (CH₃O) 102.7 (CH),104.9 (2×CH), 118.7 (CH), 123.1 (C), 133.9 (C), 134.0 (C), 136.9 (C),138.6 (C), 151.1 (C), 153. (2×C), 170.4 (CO). LC/MS (ES−) t_(r)=0.93 minm/z 451.24 (M−H)⁻; MeOH/H₂O 95/5; HPLC t_(r)=1.78 min (100%).(acetonitrile/water 90/10)

9-Benzyloxy-10-methoxy-6,7-dihydro-5H-benzo[e]tetrazolo[1,5-a]azepine298, 7-benzyloxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one299 and 7-benzyloxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one300

A solution of 6-O-benzyl-7-methoxytetralone (4.6 g, 16.2 mmol) in DCM(150 mL) was stirred at 0° C. and methanesulfonic acid (8.1 mL, 125mmol) added dropwise followed by NaN₃ (2.11 g, 32.5 mmol). The mixturewas stirred at 0° C. for 6 hours then O/N at rt. After addition ofwater, the organic layer was washed with biC(Ar)bonate, water, dried(MgSO₄), filtered and concentrated to give 5 g of crude brown solid.Column chromatography (hexane/ethyl acetate/MeOH 3:1 to 0:20:1) affordedsuccessively of9-benzyloxy-10-methoxy-6,7-dihydro-5H-benzo[c]tetrazolo[1,5-a]azepine298 (350 mg (7%)),7-benzyloxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one 299 (1.1g, 22%) and7-benzyloxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 300(1.85 g (39%)).

9-Benzyloxy-10-methoxy-6,7-dihydro-5H-benzo[c]tetrazolo azepine 298

White powder, mp 168-170° C., R_(f): 0.50 (hexane/ethyl acetate), ¹H NMR(270 MHz, DMSO-d6) δ 2.18-2.27 (2H, m), 2.97-3.02 (2H, m), 3.83 (3H, s),4.62-4.67 (2H, m), 5.16 (2H, s), 7.13 (1H, s), 7.33-7.50 (5H, m), 7.78(1H, s); ¹³C NMR (67.5 MHz, CDCl₃) δ 24.8 (CH₂), 32.5 (CH₂), 49.5 (CH₂),55.7 (CH₃O), 69.9 (CH₂), 112.2 (CH), 114.5 (C), 115.0 (CH), 128.0(2×CH), 128.1 (CH), 128.5 (2×CH), 134.3 (C), 136.6 (C), 147.5 (C), 148.4(C), 150.0 (CH), 153.6 (C). LC/MS (ES+) t_(r)=0.94 min m/z 345.11((M+Na)⁺, 100%), 323.13 (M+1)⁺; MeOH/H₂O 95/5; HPLC t_(r)=2.68 min(89.7%), 3.34 (10.3%) (CH₃CN/H₂O 70/30)

7-Benzyloxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(311)-one 299

White powder, mp 178-180° C., R_(f): 0.33 (hexane/ethyl acetate), ¹H NMR(270 MHz, DMSO-d6) δ 1.85 (2H, m), 2.67 (2H, t, J 6.9 Hz), 2.91 (2H, m),3.76 (3H, s), 5.11 (2H, s), 6.99 (1H, s), 7.07 (1H, s), 7.31-7.49 (5H,m), 7.92 (1H, t, J 5.5 Hz); ¹³C NMR (100 MHz, DMSO-d6) δ 28.3 (CH₂),29.2 (CH₂), 32.9 (CH₂), 55.7 (CH₃O), 70.3 (CH₂O) 106.7 (CH), 115.1 (CH),125.5 (C), 127.9 (CH), 128.0 (2×CH), 128.4 (2×CH), 131.9 (C), 137.2 (C),144.7 (C), 147.8 (C), 173.3 (CO). LC/MS (ES+) t_(r)=1.18 min m/z 320.10((M+Na)⁺, 100%), 298.12 (M+H)⁺; MeOH/H₂O 95/5; HPLC t_(r)=1.93 min(99.4%). (CH₃CN/H₂O 90/10)

7-Benzyloxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 300

White powder, mp 192-193° C., R_(f): 0.10 (ethyl acetate), ¹H NMR (270MHz, DMSO-d6) δ 1.85 (2H, m), 2.67 (2H, t, J 6.9 Hz), 2.91 (2H, m), 3.76(3H, s), 5.11 (2H, s), 6.99 (1H, s), 7.07 (1H, s), 7.31-7.49 (5H, m),7.92 (1H, t, J 5.5 Hz), ¹³C NMR (100 MHz, DMSO-d6) δ 29.4 (CH₂), 30.3(CH₂), 38.7 (CH₂), 55.6 (CH₃O), 69.9 (CH₂O) 102.7 (CH), 111.8 (CH),113.5 (CH), 128.0 (CH), 128.1 (CH), 128.5 (2×CH), 131.2 (C), 136.8 (C),147.4 (C), 149.4 (C), 172.0 (CO). LC/MS (ES+) t_(r)=1.18 min m/z 320.10((M+Na)⁺, 100%), 298.12 (M+H)⁺; MeOH/H₂O 95/5; HPLC t_(r)=2.52 min(100%). (CH₃CN/H₂O 70/30)

7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine 301

A solution of7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one 300(1.2 g, 4 mmol) in THF (50 mL) was cooled to 0° C. and LAH (380 mg, 10mmol) added portion wise. The mixture was refluxed for 8 hours, cooledto rt, cautiously quenched with ice and 6 ml 2M aqueous 2M NaOH thenfiltered through celite. The filtrate was extracted with EtOAc and theorganic layer was washed with water, brine, dried, filtered andconcentrated giving 0.95 g (84%) of yellow oil slowly solidifying whichupon purification by flash chromatography (EtOAc/MeOH/TEA 1/0/0 to20/1/0.5) gave 088 g (78%) of a white powder, mp=79-80° C., R_(f): 0.24(ethyl acetate/MeOH/TEA 10:1:0.5), ¹H NMR (270 MHz, CDCl₃) δ 1.41 (1H,br), 1.62-1.71 (2H, m), 2.78-2.82 (2H, m), 3.14-3.18 (2H, m), 3.85 (5H,s, MeO and CH2N), 5.11 (2H, s), 6.66 (1H, s), 6.72 (1H, s), 7.26-7.44(5H, m), ¹³C NMR (100 MHz, CDCl₃) δ 31.1 (CH₂), 35.7 (CH₂), 53.6 (CH₂),54.9 (CH₂), 56.2 (CH₂), 71.3 (CH₂O), 113.0 (CH), 116.2 (CH), 127.3 (CH),127.7 (CH), 128.4 (CH), 135.1 (C), 136.0 (C), 137.3 (C), 146.4 (C),147.1 (C). LC/MS (ES+) t_(r)=min m/z ((M+Na)⁺, 100%), (M+1)⁺; MeOH/H₂O95/5; HPLC t_(r)=3.03 min (97.5%) (CH₃CN/H₂O 70/30); HRMS (ES) calcd.for C₁₈H₂₂NO₂ (MH), 284.1651 found. 284.1645

Synthesis of2-benzyl-7-benzyloxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepines

General Method:

A solution of7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine (440 mg,1.5 mmol) and the appropriate benzyl bromide (1.65 mmol) in TEA (0.5 mL,3.6 mmol) and ethanol (2.5 mL) was heated at 130 C for 90 minutes undermicrowave energy. After addition of water (20 mL) and ethyl acetate (80mL), the organic layer was separated and washed with water, brine, dried(MgSO₄) and concentrated under reduced pressure. The resulting yellowsolid was purified by flash chromatography (hexane/ethyl acetate orDCM/ethyl acetate) to give the desired compound.

7-Benzyloxy-8-methoxy-2-(2-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine302

Cream color powder, 370 mg (61%), mp 105-106° C., R_(f): 0.36 (ethylacetate), ¹H NMR (270 MHz, CDCl₃) δ 1.72-1.77 (2H, m, CH₂), 2.75-2.80(2H, m, CH₂), 3.05-3.09 (2H, m, CH₂), 3.55 (2H, s, CH₂), 3.80 (3H, s,CH₃O), 3.82 (3H, s, CH₃O), 3.83 (2H, s, CH₂), 5.12 (2H, s, CH₂), 6.61(1H, s, ArH), 6.72 (1H, s, ArH), 6.88 (1H, dd, J 8.3 and 1.0 Hz, ArH),6.91 (1H, dt, J 7.4 and 1.0 Hz), 7.21 (1H, dd, J 8.2 and 1.7 Hz, ArH),7.26-7.46 (6H, s,ArH). ¹³C NMR (67.5 MHz, CDCl₃) δ 26.0 (CH₂), 35.8(CH₂), 51.6 (CH₂), 55.5 (CH₂), 56.3 (CH₂), 58.8 (CH₃O), 59.6 (CH₃O),71.4 (CH₂O), 110.5 (CH), 114.7 (CH), 115.7 (CH), 127.4 (2×CH), 127.6(C), 127.8 (CH), 128.0 (CH), 128.6 (2×CH), 130.6 (CH), 132.7 (C), 135.6(C), 137.5 (C), 146.6 (C), 147.2 (C), 159.9 (C). LC/MS (ES+) t_(r)=1.45min m/z 404.19 ((MH)⁺, 100%); MeOH/H₂O 95/5; HPLC t_(r)=6.74 min (99.5%)(CH₃CN/H₂O 90/10)

7-Benzyloxy-8-methoxy-2-(3-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzoazepine303

White powder, 410 mg (68%), mp 92-93° C., R_(f): 0.5 (ethyl acetate), ¹HNMR (270 MHz, CDCl₃) δ 1.68-1.74 (2H, m, CH₂), 2.77-2.81 (2H, m, CH₂),3.10-3.14 (2H, m, CH₂), 3.51 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 3.80 (5H,s, CH₂ and CH₃O), 5.13 (2H, s, CH₂), 6.48 (1H, s, ArH), 6.73 (1H, s,ArH), 6.77-6.88 (3H, m, ArH), 7.21 (1H, t, J 8.2 Hz, ArH), 7.27-7.46(5H, s, Ph). ¹³C NMR (67.5 MHz, CDCl₃) δ 25.4 (CH₂), 35.8 (CH₂), 55.3(CH₂), 56.2 (CH₂), 57.6 (CH₂), 58.7 (CH₂O), 59.2 (CH₃O), 71.4 (CH₃O),112.7 (CH), 114.4 (CH), 114.7 (CH), 115.6 (CH), 121.5 (CH), 127.5(2×CH), 127.9 (CH), 128.6 (2×CH), 129.1 (CH), 132.2 (C), 135.4 (C),137.5 (C), 141.1 (C), 146.6 (C), 147.1 (C), 159.8 (C). LC/MS (ES+)t_(r)=1.38 min m/z 404.25 ((MH)⁺, 100%); MeOH/H₂O 95/5; HPLC t_(r)=4.08min (98.4%) (CH₃CN/H₂O 90/10)

7-Benzyloxy-8-methoxy-2-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine304

Light yellow powder, 350 mg (58%), mp 87-88° C., R_(f): 0.31 (ethylacetate), ¹H NMR (270 MHz, CDCl₃) δ 1.66-1.74 (2H, m, CH₂), 2.77-2.81(2H, m, CH₂), 3.08-3.12 (2H, m, CH₂), 3.48 (2H, s, CH₂), 3.78 (2H, s,CH₂), 3.80 (6H, s, 2×CH₃O), 5.13 (2H, s, CH₂), 6.48 (1H, s, ArH), 6.73(1H, s, ArH), 6.85 (2H, d, J 8.5 Hz, ArH), 7.21 (2H, d, J 8.5 Hz, ArH),7.27-7.47 (5H, s, Ph). ¹³C NMR (67.5 MHz, CDCl₃) δ 25.4 (CH₂), 35.8(CH₂), 55.4 (CH₂), 56.2 (CH₃O), 56.9 (CH₂), 58.6 (CH₂), 59.0 (CH₃O),71.3 (CH₂), 113.6 (2×CH), 114.7 (CH), 115.6 (CH), 127.5 (2×CH), 127.9(CH), 128.6 (2×CH), 130.4 (2×CH), 131.3 (C), 132.1 (C), 135.5 (C), 137.5(C), 146.6 (C), 147.1 (C), 158.7 (C). LC/MS (ES+) t_(r)=1.40 min m/z404.13 ((MH)⁺, 100%); MeOH/H₂O 95/5; HPLC t_(r)=5.13 min (97.8%)(CH₃CN/H₂O 90/10).

7-Benzyloxy-8-methoxy-2-(3,4,5-trimethoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine305

White solid, 420 mg (58%) mp 44-46° C., R_(f): 0.26 (ethyl acetate), ¹HNMR (270 MHz, CDCl₃) δ 1.67-1.75 (2H, m), 2.77-2.81 (2H, m, CH₂),3.10-3.13 (2H, m, CH₂), 3.47 (2H, s, CH₂), 3.76 (3H, s, CH₃O), 3.79 (2H,s, CH₂), 3.82 (6H, s, 2×CH₃O), 3.84 (3H, s, CH₃O), 5.12 (2H, s, CH₂),6.45 (1H, s, ArH), 6.53 (2H, s, ArH), 6.73 (1H, m, ArH), 7.26-7.46 (5H,s, Ph); ¹³C NMR (67.5 MHz, CDCl₃) δ 25.4 (CH₂), 35.8 (CH₂), 56.2 (CH₃),56.3 (2×CH₃), 55.8 (CH₂), 58.5 (CH₂), 59.2 (CH₃O), 61.0 (CH₂), 71.3(CH₂), 105.5 (2×CH), 114.7 (CH), 115.6 (CH), 127.5 (2×CH), 127.9 (CH),128.6 (2×CH), 132.2 (C), 135.2 (C), 135.5 (C), 136.7 (C), 137.5 (C),146.7 (C), 147.1 (C), 153.2 (2×C). LC/MS (ES+) t_(r)=2.05 min m/z 464.28((MH)⁺, 100%); MeOH/H₂O 95/5; HPLC t_(r)=1.99 min (94.8%) and 2.36 (5%),idem? (CH₃CN/H₂O 90/10).

Synthesis of2-benzyl-7-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[e]azepines

General Method:

A solution of2-benzyl-7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepines(1 mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C(40 mg) and stirred under an atmosphere of hydrogen. The reaction wasmonitored by TLC. Upon completion, the resultant suspension was filteredthrough celite, washed with ethyl acetate and then evaporated underreduced pressure. The crude mixture was purified by flash chromatography(hexane/ethyl acetate) and the resulting solid stirred in diethyl ether,filtered and dried under vacuum.

7-Hydroxy-8-methoxy-2-(2-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine306

White powder, 240 mg (77%), mp 136-137° C., R_(f): 0.25 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 1.72-1.78 (2H, m, CH₂), 2.78-2.82 (2H, m,CH₂), 3.05-3.09 (2H, m, CH₂), 3.54 (2H, s, CH₂), 3.79 (3H, s, CH₃O),3.82 (3H, s, CH₃O), 3.84 (2H, s, CH₂), 5,48 (1H, br, OH), 6.56 (1H, s,ArH), 6.73 (1H, m, ArH), 6.85 (1H, d, J 8.5 Hz, ArH), 6.90 (1H, t, J 7.4Hz, ArH), 7.18-7.22 (1H, m, ArH), 7.32 (1H, d, J 7.4 Hz); ¹³C NMR (67.5MHz, CDCl₃) δ 25.6 (CH₂), 35.5 (CH₂), 51.3 (CH₂), 55.4 (CH₃), 58.1(CH₃), 58.5 (CH₂), 59.6 (CH₂), 110.3 (CH), 113.1 (CH), 115.5 (CH), 120.1(CH), 127.5 (C), 127.9 (CH), 130.5 (CH), 131.3 (C), 136.3 (C), 143.9(C), 157.8 (C). LC/MS (ES+) t_(r)=1.12 min m/z 314.06 ((MH)⁺, 100%);MeOH/H₂O 95/5; HPLC t_(r)=4.45 min (99.6%) (CH₃CN/H₂O 90/10)

7-Hydroxy-8-methoxy-2-(3-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e]azepine307

White powder, 225 mg (72%), mp 114-115° C., R_(f): 0.36 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 1.65-1.74 (2H, m, CH₂), 2.77-2.82 (2H, m,CH₂), 3.08-3.13 (2H, m, CH₂), 3.50 (2H, s, CH₂), 3.78 (5H, s, CH₂ andCH₃O), 3.79 (3H, s, CH₃O), 5,48 (1H, br, OH), 6.41 (1H, s, ArH), 6.73(1H, m, ArH), 6.77-6.87 (3H, m, ArH), 7.21 (1H, t, J 7.5 Hz); ¹³C NMR(67.5 MHz, CDCl₃) δ 25.2 (CH₂), 35.4 (CH₂), 55.2 (CH₂), 56.0 (CH₃), 57.2(CH₃), 58.6 (CH₂), 59.0 (CH₂), 112.5 (CH), 113.2 (CH), 114.3 (CH), 115.5(CH), 121.4 (CH), 129.0 (CH), 130.8 (C), 136.1 (C), 141.0 (C), 143.8(C), 143.9 (C), 159.6 (C). LC/MS (ES+) t_(r)=1.05 min m/z 313.99 ((MH)⁺,100%); MeOH/H₂O 95/5; HPLC t_(r)=2.67 min (100%) (CH₃CN/H₂O 90/10)

7-Hydroxy-8-methoxy-2-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine308

White powder, 140 mg (45%), mp 105-107° C., R_(f): 0.28 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 1.68-1.74 (2H, m, CH₂), 2.76-2.81 (2H, m,CH₂), 3.07-3.11 (2H, m, CH₂), 3.47 (2H, s, CH₂), 3.78 (3H, s, CH₃O),3.80 (5H, s, CH₂ and CH₃O), 5,49 (1H, br, OH), 6.43 (1H, s, ArH), 6.72(1H, m, ArH), 6.84 (2H, d, J 8.5 Hz, ArH), 7.19 (2H, d, J 8.5 Hz, ArH);¹³C NMR (67.5 MHz, CDCl₃) δ 25.2 (CH₂), 35.5 (CH₂), 55.4 (CH₂), 56.1(CH₃), 56.6 (CH₃), 58.5 (CH₂), 58.6 (CH₂), 113.4 (CH), 113.6 (2×CH),115.7 (CH), 130.4 (2×CH), 131.0 (C), 136.2 (C), 144.0 (C), 144.2 (C),158.7 (C). LC/MS (ES+) t_(r)=1.13 min m/z 314.18 ((MH)⁺, 100%); MeOH/H₂O95/5; HPLC t_(r)=2.96 min (99.4%) (CH₃CN/H₂O 90/10)

7-Hydroxy-8-methoxy-2-(3,4,5-trimethoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine309

Light yellow powder, 280 mg (75%), mp 46-48° C., R_(f): 0.15 (ethylacetate), ¹H NMR (270 MHz, CDCl₃) δ 1.68-1.75 (2H, m, CH₂), 2.78-2.82(2H, m, CH₂), 3.09-3.13 (2H, m, CH₂), 3.46 (2H, s, CH₂), 3.75 (3H, s,CH₃O), 3.79 (2H, s, CH₃O), 3.82 (6H, s, 2CH₃O), 3.83 (3H, s, CH₃O), 5.52(1H, br, OH), 6.38 (1H, s, ArH), 6.52 (2H, s, ArH), 6.73 (1H, m, ArH),¹³C NMR (67.5 MHz, CDCl₃) δ 25.2 (CH₂), 35.5 (CH₂), 56.2 (2×CH₃), 57.5(CH₃), 58.6 (CH₂), 59.0 (CH₃O), 61.0 (CH₂), 105.5 (2×CH), 113.3 (CH),115.6 (CH), 130.8 (C), 135.2 (C), 136.2 (C), 136.6 (C), 143.9 (C), 144.0(C), 153.1 (2×C). LC/MS (ES+) t_(r)=1.09 min m/z 374.08 ((MH)⁺, 100%);MeOH/H₂O 95/5; HPLC t_(r)=3.04 min (98.3%) (CH₃CN/H₂O 90/10)

Synthesis of2-benzyl-8-methoxy-7-O-sulfamoyl-2,3,4,5-tetrahydro-1H-benzo[c]azepines

General Method:

A solution of2-benzyl-7-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepines (0.5mmol) and sulfamoyl chloride (1 mmol) in DMA (1 mL) was stirred at rtunder nitrogen for 24 hours. After addition of water (5 mL) and sodiumhydrogenoC(Ar)bonate (170 mg, 2 mmol) the organics were extracted intoethyl acetate (2×50 mL), the organic layers washed with water and brine,then dried (MgSO₄) and evaporated. The crude product was purified byflash chromatography (hexane/ethyl acetate) and the resulting solidstirred in diethyl ether, filtered and dried under vacuum.

8-Methoxy-2-(2-methoxybenzyl)-7-O-sulfamoyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylsulfamate 310

White powder, 76 mg (39%), mp=79-80° C., R_(f): 0.21 (ethyl acetate), ¹HNMR (270 MHz, CDCl₃) δ 1.74-1.78 (2H, m, CH₂), 2.79-2.83 (2H, m, CH₂),3.03-3.06 (2H, m, CH₂), 3.58 (2H, s, CH₂), 3.79 (3H, s, CH₃O), 3.81 (3H,s, CH₃O), 3.85 (2H, s, CH₂), 4.96 (2H, br, NH₂), 6.69 (1H, s, ArH),6.84-6.94 (2H, m), 7.11 (1H, s, ArH), 7.20-7.32 (2H, m); LC/MS (ES+)t_(r)=1.00 min m/z 393.10 ((M+H)⁺, 100%); MeOH/H₂O 95/5

8-Methoxy-2-(3-methoxybenzyl)-7-O-sulfamoyl-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylsulfamate 311

White powder, 165 mg (84%), mp=62-64° C., R_(f): 0.41 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 1.70-1.75 (2H, m, CH₂), 2.80-2.83 (2H, m,CH₂), 3.07-3.10 (2H, m, CH₂), 3.52 (2H, s, CH₂), 3.77 (3H, s, CH₃O),3.78 (3H, s, CH₃O), 3.79 (2H, s, CH₂), 5.11 (2H, br, NH₂), 6.55 (1H, s,ArH), 6.77-6.85 (3H, m), 7.10 (1H, s, ArH), 7.21 (1H, t, J 7.7 Hz);LC/MS (ES+) t_(r)=0.91 min m/z 393.10 ((M+H)⁺, 100%); MeOH/H₂O 95/5

8-Methoxy-2-(4-methoxybenzyl)-7-O-sulfamoyl-2,3,4,5-tetrahydro-1H-benzo[e]azepin-7-ylsulfamate 312

White powder, 150 mg (77%), mp=64-65° C., R_(f): 0.27 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 1.68-1.75 (2H, m, CH₂), 2.79-2.83 (2H, m,CH₂), 3.04-3.08 (2H, m, CH₂), 3.50 (2H, s, CH₂), 3.78 (3H, s, CH₃O),3.79 (5H, s, CH₂ and CH₃O), 5.28 (2H, s, NH₂), 6.57 (1H, s, ArH), 6.83(2H, d, J 8.5 Hz), 7.10 (1H, s, ArH), 7.19 (1H, d, J 8.5 Hz); Hz); LC/MS(ES+) t_(r)=0.94 min m/z 393.04 ((M+H)⁺, 100%); MeOH/H₂O 95/5

8-Methoxy-7-O-sulfamoyl-2-(3,4,5-trimethoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-ylsulfamate 313

White powder, 170 mg (76%), mp=78-80° C., R_(f): 0.11 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 1.70-1.77 (2H, m, CH₂), 2.81-2.86 (2H, m,CH₂), 3.08-3.12 (2H, m, CH₂), 3.48 (2H, s, CH₂), 3.76 (3H, s, CH₃O),3.78 (2H, s, CH₂), 3.81 (6H, s, 2×CH₃O), 3.82 (3H, s, CH₃O), 5,01 (2H,br, NH₂), 6.50 (3H, s, ArH), 7.11 (1H, s, ArH); ¹³C NMR (67.5 MHz,CDCl₃) δ 25.1 (CH₂), 35.1 (CH₂), 56.2 (2×CH₃), 56.3 (CH₂), 58.1 (CH₂),58.8 (2×CH₃O), 61.0 (CH₂), 105.5 (2×CH), 115.1 (CH), 124.7 (CH), 134.6(C), 136.4 (C), 136.8 (C), 137.2 (C), 139.6 (C), 148.8 (C), 153.2 (2×C).LC/MS (ES−) t_(r)=0.92 min m/z 451.11 ((M−H)⁻, 100%); MeOH/H₂O 95/5;HPLC t_(r)=1.86 min (100%) (CH₃CN/H₂O 90/10)

Synthesis of2-benzyl-7-benzyloxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-ones

A solution of7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one (297mg, 1.0 mmol) and NaH (80 mg, 2 mmol) was stirred in DMF (5 mL) for 10minutes at rt and the appropriate benzyl bromide or benzyl chloride (1.1mmol) added. The mixture was stirred o/n at rt. After addition of waterthe organics extracted with ethyl acetate, washed with water, brine,dried (MgSO₄), filtered and concentrated. The crude yellow oil waspurified by flash chromatography (hexane/EtOAc 1:0 to 1:1) and theresultant solid was stirred in Et₂O, filtered and dried under vacuum.

7-Benzyloxy-8-methoxy-2-(3,4,5-trimethoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one314

White powder, 270 mg (57%), mp 134-135° C., R_(f:) 0.17 (hexane/ethylacetate 1:1) ¹H NMR (270 MHz, CDCl₃) δ 1.69-1.79 (2H, m, CH₂), 2.61 (2H,t, J 7.2 Hz, CH₂), 3.20 (2H, t, J 6.3 Hz, CH₂), 3.83 (3H, s, CH₃O), 3.84(6H, s), 3.90 (3H, s, CH₃O), 4.68 (2H, s, CH₂), 5.15 (2H, s, CH₂), 6.59(2H, s, ArH), 6.63 (1H, s, ArH), 7.25-7.44 (6H, s, ArH); ¹³C NMR (67.5MHz, CDCl₃) δ 29.9 (CH₂), 30.1 (CH₂), 46.2 (CH₂), 50.9 (CH₂), 56.2(3×CH₃), 61.0 (CH₃), 71.0 (CH₂), 105.3 (2×CH), 112.3 (CH), 113.8 (CH),127.4 (2×CH), 128.1 (CH), 128.3 (C), 128.7 (2×CH), 130.8 (C), 134.2 (C),136.7 (C), 137.4 (C), 148.4 (C), 150.0 (C), 153.4 (2×C), 171.4 (CO).LC/MS (ES+) t_(r)=1.60 min m/z 500.24 ((M+Na)⁺, 100%), 478.26 (M+H)⁺;MeOH/H₂O 95/5; HPLC t_(r)=3.72 min (99.3%), (CH₃CN/H₂O 90/10)

Synthesis of2-benzyl-7-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-ones

General Method:

A solution of2-benzyl-7-benzyloxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(1 mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C(40 mg) and stirred under an atmosphere of hydrogen. The reaction wasmonitored by TLC. Upon completion, the resultant suspension was filteredthrough celite, washed with ethyl acetate and then evaporated underreduced pressure. The resulting solid was stirred in diethyl ether,filtered and dried under vacuum or purified by flash chromatography(hexane/ethyl acetate) and the resultant solid stirred in diethyl ether,filtered and dried under vacuum.

7-Hydroxy-8-methoxy-2-(3,4,5-trimethoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one316

White powder, 305 mg (79%) mp 172 173-° C., R_(f:) 0.11 (hexane/ethylacetate 1:1), 0.34 (EtOAc), ¹H NMR (270 MHz, CDCl₃) δ 1.70-1.82 (2H, m,CH₂), 2.64 (2H, t, J 7.2 Hz, CH₂), 3.21 (2H, t, J 6.5 Hz, CH₂), 3.83(3H, s, CH₃O), 3.84 (6H, s, 2×CH₃O), 3.90 (3H, s, CH₃O), 4.68 (2H, s,CH₂), 5.86 (1H, s, OH), 6.59 (2H, s, ArH), 6.67 (1H, s, ArH), 7.25 (1H,s, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ 29.8 (CH₂), 29.9 (CH₂), 46.2 (CH₂),51.0 (CH₂), 56.2 (3×₃), 61.0 (CH₃), 105.3 (2×CH), 111.5 (CH), 114.6(CH), 127.5 (C), 131.8 (C), 134.2 (C), 137.3 (C), 145.4 (C), 147.7 (C),153.4 (2×C), 171.5 (CO). LC/MS (ES−) t_(r)=0.91 min m/z 386.05 ((M−H)⁻,100%); MeOH/H₂O 95/5; HPLC t_(r)=1.70 min (100%), (CH₃CN/H₂O 90/10)

Synthesis of2-benzyl-8-methoxy-7-O-sulfamoyl-2,3,4,5-tetrahydro-1H-benzo[e]azepin-1-ones

A solution of2-benzyl-7-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepine-1-one(0.5 mmol) and sulfamoyl chloride (1 mmol) in DMA (1 mL) was stirred atrt under nitrogen for 24 hours. After addition of water (5 mL) theorganics were extracted into ethyl acetate, the organic layers washedwith water and brine, then dried (MgSO₄) and evaporated. The crudeproduct was purified by flash chromatography (hexane/ethyl acetate) andthe resulting solid stirred in diethyl ether, filtered and dried undervacuum.

8-methoxy-7-O-sulfamoyl-2-(3,4,5-trimethoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e]azepin-1-one317

White powder, 185 mg (79%), mp 211-213° C., R_(f): 0.37 (EtOAc), ¹H NMR(270 MHz, DMSO-d6) δ 1.72-1.77 (2H, m, CH₂), 2.63 (2H, t, J 6.6 Hz,CH₂), 3.18 (2H, t, J 7.1 Hz, CH₂), 3.65 (3H, s, CH₃O), 3.77 (6H, s,2×CH₃O), 3.83 (3H, s, CH₃O), 4.63 (2H, s, CH₂), 6.70 (2H, s, ArH), 7.18(1H, s, ArH), 7.29 (1H, s, ArH), 8.01 (2H, s, NH₂); ¹³C NMR (100 MHz,DMSO-d₆) δ 28.7 (CH₂), 28.9 (CH₂), 45.3 (CH₂), 49.6 (CH₂), 55.9 (2×CH₃),56.1 (CH₃), 60.1 (CH₃), 105.3 (2×CH), 113.2 (CH), 123.1 (CH), 129.7 (C),134.2 (C), 134.6 (C), 136.7 (C), 140.0 (C), 150.3 (C), 152.9 (2×C),169.2 (CO). HPLC t_(r)=1.63 min (100%), (CH₃CN/H₂O 90/10)

Synthesis of1-benzyl-7-benzyloxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

General Method:

A solution of7-benzyloxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one (297 mg,1.0 mmol) and NaH (80 mg, 2 mmol) was stirred in DMF (5 mL) for 10minute at rt and the appropriate benzyl bromide or benzyl chloride (1.1mmol) added. The mixture was stirred o/n at rt. After addition of waterthe organics extracted with ethyl acetate, washed with water, brine,dried (MgSO₄), filtered and concentrated. The crude yellow oil waspurified by flash chromatography (hexane/EtOAc 1:0 to 1:1) and theresultant solid stirred in Et₂O, filtered and dried under vacuum.

7-benzyloxy-8-methoxy-1-(3,4,5-trimethoxybenzyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one318

White powder, 225 mg (47%), mp 129-130° C., R_(f): 0.21 (hexane/ethylacetate 1:1), ¹H NMR (270 MHz, CDCl₃) δ 2.05-2.40 (6H, m, 3×CH₂), 3.72(6H, s, 2×CH₃O), 3.78 (3H, s, CH₃O), 3.82 (3H, s, CH₃O), 4.86 (2H, br,CH₂), 5.10 (2H, s, CH₂), 6.44 (2H, s, ArH), 6.65 (1H, s, ArH), 6.69 (1H,s, ArH), 7.27-7.43 (5H, s, Ph), ¹³C NMR (67.5 MHz, CDCl₃) δ 29.3 (CH₂),29.5 (CH₂), 33.3 (CH₂), 51.4 (CH₂), 56.1 (2×CH₃), 56.3 (CH₃), 60.9(CH₂), 71.3 (CH₂), 105.3 (2×CH), 107.8 (CH), 114.5 (CH), 127.4 (2×CH),128.1 (CH), 128.3 (C), 128.7 (2×CH), 133.9 (C), 135.3 (C), 136.9 (C),137.2 (C), 146.4 (C), 148.7 (C), 153.2 (2×C), 173.6 (CO). LC/MS (ES+)t_(r)=1.75 min m/z 500.30 ((M+Na)⁺, 100%), 478.26 (M+H)⁺; MeOH/H₂O 95/5HPLC t_(r)=1.99 min (98.2%), (CH₃CN/H₂O 90/10)

Synthesis of1-benzyl-7-hydroxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

General Method:

A solution of2-benzyl-7-(benzyloxy)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[c]azepin-1-one(1 mmol) in THF (20 mL) and methanol (20 mL) was treated with 10% Pd/C(40 mg) and stirred under an atmosphere of hydrogen. The reaction wasmonitored by TLC. Upon completion, the resultant suspension was filteredthrough celite, washed with ethyl acetate and then evaporated underreduced pressure. The resulting solid was stirred in diethyl ether,filtered and dried under vacuum or purified by flash chromatography(hexane/ethyl acetate) then stirred in diethyl ether, filtered and driedunder vacuum.

7-Hydroxy-8-methoxy-1-(3,4,5-trimethoxybenzyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one319

White powder, 305 mg (79%), mp 170-171° C., R_(f): 0.61 (ethyl acetate),¹H NMR (270 MHz, CDCl₃) δ 2.00-2.16 (2H, m, CH₂), 2.26-2.32 (2H, m,CH₂), 2.39-2.46 (2H, m, CH₂), 3.75 (6H, s, 2×CH₃O), 3.76 (3H, s, CH₃O),3.79 (3H, s, CH₃O), 4.86 (2H, br, CH₂), 5.57 (1H, s, OH), 6.45 (2H, s,ArH), 6.62 (1H, s, ArH), 6.69 (1H, s, ArH); ¹³C NMR (67.5 MHz, CDCl₃) δ29.2 (CH₂), 29.3 (CH₂), 33.2 (CH₂), 51.6 (CH₂), 56.2 (3×CH₃), 61.0(CH₂), 105.3 (2×CH), 106.5 (CH), 114.8 (CH), 129.1 (C), 134.0 (C), 134.3(C), 137.1 (C), 143.9 (C), 145.5 (C), 153.2 (2×C), 173.8 (CO). LC/MS(ES−) t_(r)=0.90 min m/z 386.18((M−H)⁻, 100%); MeOH/H₂O 95/5; HPLCt_(r)=1.61 min (100%), (CH₃CN/H₂O 90/10)

Synthesis of1-benzyl-8-methoxy-7-O-sulfamoyl-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one

A solution of1-benzyl-7-hydroxy-8-methoxy-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one(0.5 mmol) and sulfamoyl chloride (1 mmol) in DMA (1 mL) was stirred atrt under nitrogen for 24 hours. After addition of water (5 mL) theorganics were extracted into ethyl acetate, the organic layers washedwith water and brine, then dried (MgSO₄) and evaporated. The crudeyellow solid was stirred in diethyl ether, filtered and dried undervacuum.

8-methoxy-7-O-sulfamoyl-1-(3,4,5-trimethoxybenzyl)-4,5-dihydro-1H-benzo[b]azepin-2(3H)-one320

White powder, 225 mg (96%), mp 172-173° C., R_(f): 0.48 (ethyl acetate),¹H NMR (270 MHz, DMSO-d6) δ 2.00-2.16 (2H, m, CH₂), 2.01-2.25 (4H, m,2×CH₂), 2.45-2.50 (2H, m, CH₂), 3.58 (3H, s, CH₃O), 3.66 (3H, s,2×CH₃O), 3.78 (3H, s, CH₃O), 4.99 (2H, br, CH₂), 6.51 (2H, s, ArH), 7.13(1H, s, ArH), 7.17 (1H, s, ArH), 7.94 (2H, s, NH₂); ¹³C NMR (100 MHz,DMSO-d₆) δ 28.6 (2×CH₂), 32.9 (CH₂), 49.3 (CH₂), 55.7 (2×CH₃), 56.2(CH₃), 60.0 (CH₃), 105.2 (2×CH), 108.6 (CH), 123.3 (CH), 127.4 (C),133.8 (C), 136.2 (C), 136.4 (C), 140.1 (C), 150.7 (C), 152.7 (2×C),172.1 (CO). LC/MS (ES−) t_(r)=0.85 min m/z 465.10 ((M−H)⁻, 100%);MeOH/H₂O 95/5 HPLC t_(r)=1.43 min (99.8%), (CH₃CN/H₂O 90/10)

6-Benzyloxy-7-methoxy-2-(2,4,6-trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolineF1

A solution of 6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (539mg, 2 mmol) and 2,4,6-trimethoxybenzoic acid in dry DCM (25 mL) wasstirred at 0° C. under nitrogen before EDCI (767 mg, 4 mmol) was addedportion wise. The mixture was stirred for 1 hour at 0° C. then 1 hour atrt. After addition of DCM (25 mL), the organic layer was washed withwater, 10% citric acid, water, brine, dried (MgSO₄), filtered andconcentrated. Column chromatography (hexane/EtOAc 5/1 to 0/1) afforded0.73 g of a white powder (79%), m.p. 70-72° C., 2-rotamers present by ¹HNMR: set 1: ¹H NMR (270 MHz, CDCl₃) δ 2.62 (2H, t, J=5.5 Hz), 3.44 (2H,t, J=5.5 Hz), 3.75 (6H, s), 3.82 (3H, s), 3.86 (3H, s), 4.85 (2H, s),5.10 (2H, s), 6.11 (2H, s), 6.60 (1H, s), 6.68 (1H, s), 7.28-7.44 (5H,m); set 2: ¹H NMR (270 MHz, CDCl₃) δ 2.78 (2H, t, J=5.8 Hz), 3.66 (6H,s), 3.78 (3H, s), 3.82 (3H, s), 3.96 (2H, t, J=5.8 Hz), 4.32 (2H, s),5.11 (2H, s), 6.10 (2H, s), 6.41 (1H, s), 6.67 (1H, s), 7.28-7.44 (5H,m). HRMS (ES) calcd. for C₂₇H₃₀NO₆ (M⁺+H), 464.2068 found 464.2070 HPLC:tr=2.40 (99.6%) CH₃CN/H₂O 90/10

6-Benzyloxy-7-methoxy-2-(2,4,6-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF2

A solution of F1 (720 mg, 1.55 mmol) in THF (20 mL) was cooled to 0° C.before LiAlH₄ (76 mg, 2.0 mmol) was added portion wise. The mixture wasrefluxed for 2 hours, cooled to 0° C. and 15% aqueous NaOH (1 mL) wasadded drop wise. The mixture was stirred for 30 minutes, MgSO₄ added andthe mixture stirred another 30 minutes, filtered and concentrated. Thecrude product (700 mg) was purified by flash chromatography(hexane/EtOAc 10/1 to 0/1) yielding 500 mg of a white powder (72%).m.p.: 129-131° C., ¹H NMR (270 MHz, CDCl₃) δ 2.67-2.78 (4H, m), 3.59(2H, s), 3.69 (2H, s), 3.80 (6H, s), 3.81 (6H, s), 5.07 (2H, s), 6.14(2H, s), 6.50 (1H, s), 6.56 (1H, s), 7.24-7.41 (5H, m); ¹³C NMR (100MHz, CDCl₃) δ 28.6 (CH₂), 48.8 (CH₂), 50.5 (CH₂), 55.2 (CH₂), 55.4(CH₃), 55.9 (2×CH₃), 56.2 (CH₃), 56.6 (CH₃), 71.2 (CH₂), 90.6 (2×CH),107.2 (C), 110.4 (CH), 114.4 (CH), 126.6 (C), 127.4 (2×CH), 127.7 (CH),128.5 (2×CH), 137.5 (C), 146.5 (C), 147.8 (C), 160.2 (2×C) and 160.6(C). HRMS (ES) calcd. for C₂₇H₃₂NO₅ (MH⁺), 450.2275 found 450.2263

see Method 1 of the “Synthesis of6-hydroxy-2-benzyl-1,2,3,4-tetrahydroisoquinolines”7-Methoxy-2-(2,4,6-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-olF3

260 mg, (71%), light yellow powder, m.p. 150-151° C., ¹H NMR (270 MHz,CDCl₃) δ 2.70-2.77 (4H, m), 3.58 (2H, s), 3.69 (2H, s), 3.80 (9H, s),3.81 (3H, s), 5.56 (1H, br), 6.13 (2H, s), 6.44 (1H, s), 6.56 (1H, s);¹³C NMR (100 MHz, CDCl₃) δ27.1 (CH₂), 48.0 (CH₂), 49.7 (CH₂), 55.3(CH₂), 55.4 (CH₃), 55.8 (2×CH₃), 56.2 (CH₃), 56.6 (CH₃), 90.5 (2×CH),103.8 (C), 108.9 (C), 114.2 (CH), 125.9 (C), 126.1 (C), 144.2 (C), 145.1(C), 160.2 (2×C) and 160.6 (C). HRMS (ES) calcd. for C₂₀H₂₆NO₅ (MH⁺),360.1805 found 360.1790. HPLC: tr=1.01 (99.5%) CH₃CN/H₂O 90/10

see “Synthesis of6-O-sulfamoyl-2-benzyl-1,2,3,4-tetrahydroisoquinolines”

7-Methoxy-6-O-sulfamoyl-2-(2,4,6-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF4

165 mg, (76%), yellow powder, m. p. 151-153° C., ¹H NMR (270 MHz,CDCl₃/CD₃OD 10:1) δ 2.72-2.76 (4H, m), 3.24 (2H, br), 2.58 (2H, s), 3.72(2H, s), 3.75 (9H, s), 3.76 (3H, s), 6.09 (2H, s), 6.53 (1H, s), 7.00(1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 27.3 (CH₂), 48.4 (CH₂), 49.7 (CH₂),54.6 (CH₂), 55.2 (CH₃), 55.5 (2×CH₃), 56.0 (CH₃), 56.6 (CH₃), 90.2(2×CH), 103.8 (C), 110.8 (CH), 123.4 (CH), 126.5 (C), 133.8 (C), 137.3(C), 149.4 (C), 160.0 (2×C) and 160.9 (C). HRMS (Electrospray) calcd.for C₂₀H₂₇N₂O₇S (MH⁺), 439.1533 found 439.1521. HPLC: tr=0.99 (98.0%)CH₃CN/H₂O 90/10

see Method 1 for the “Synthesis of6-(benzyloxy)-2-benzyl-1,2,3,4-tetrahydroisoquinolines”

6-Benzyloxy-2-(3,5-difluorobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolineF5

475 mg, (80%), white powder, m.p. 116-117° C., ¹H NMR (270 MHz, CDCl₃) δ2.67-2.79 (4H, m), 3.53 (2H, s), 3.62 (2H, s), 3.82 (3H, s), 5.10 (2H,s), 6.50 (1H, s), 6.63 (1H, s), 6.69 (1H, tt, J=9.0 and 2.5 Hz),6.90-6.94 (2H, m), 7.28-7.44 (5H, m); ¹³C NMR (10 MHz, CDCl₃) δ 28.6(CH₂), 50.8 (CH₂), 55.6 (CH₂), 56.1 (CH₃), 61.9 (CH₂), 71.1 (CH), 102.4(CH, t, J=25.3 Hz), 110.1 (CH), 111.3 (2×CH), dd, J_(CF)=18.4 and 6.9Hz), 114.4 (CH), 126.0 (C), 127.0 (C), 127.2 (2×CH), 127.7 (CH), 128.5(2×CH), 137.3 (CH), 143.0 (C, t, J_(CF)=9.2 Hz), 146.8 (C), 148.0 (C),163.1 (2×C, dd, J_(CF)=248.4 and 13.0 Hz). HRMS (Electrospray) calcd.for C₂₄H₂₄F₂NO₂ (MH⁺), 396.1770 found 396.1755. HPLC t_(r)=4.29 min(99.7%), (CH₃CN/H₂O 90/10)

Method 1 of the “Synthesis of6-hydroxy-2-benzyl-1,2,3,4-tetrahydroisoquinolines”2-(3,5-Difluorobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol F6

220 mg (72%), light yellow powder, m.p. 110-111° C., ¹H NMR (270 MHz,CDCl₃) δ 2.68-2.72 (2H, m), 2.77-2.81 (2H, m), 3.52 (2H, s), 3.62 (2H,s), 3.81 (3H, s), 5.51 (1H, br), 6.45 (1H, s), 6.66 (1H, s), 6.70 (1H,dt, J=8.9 and 2.5 Hz), 6.90-6.95 (2H, m); ¹³C NMR (100 MHz, CDCl₃) δ28.4 (CH₂), 50.9 (CH₂), 55.6 (CH₂), 56.0 (CH₃), 61.8 (CH₂), 102.4 (CH,t, J=25.3 Hz), 108.7 (CH), 111.4 (2×CH), dd, J_(CF)=18.4 and 6.9 Hz),114.2 (CH), 125.7 (C), 126.8 (C), 143.0 (C, t, J_(CF)=9.2 Hz), 144.1(C), 144.9 (C), 163.1 (2×C, dd, J_(CF)=248.4 and 13.0 Hz). HRMS (ES)calcd. for C₁₇H₁₈F₂NO₂ (MH⁺), 306.1300 found 306.1292. HPLC t_(r)=2.37min (100%), (CH₃CN/H₂O 90/10)

see “Synthesis of6-O-sulfamoyl-2-benzyl-1,2,3,4-tetrahydroisoquinolines”

2-(3,5-Difluorobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline6-O-sulfamate F7

120 mg (79%), m.p. 142-143° C., ¹H NMR (270 MHz, CDCl₃) δ 2.72 (2H, t,J=5.6 Hz), 2.83 (2H, t, J=5.6 Hz), 3.56 (2H, s), 3.63 (2H, s), 3.82 (3H,s), 5.01 (2H, br), 6.60 (1H, s), 6.70 (1H, tt, J=9.0 and 2.2 Hz), 6.91(2H, d, J=6.3 Hz), 7.08 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 28.2 (CH₂),50.6 (CH₂), 55.7 (CH₂), 56.4 (CH₃), 61.8 (CH₂), 102.7 (CH, t, J=25.3Hz), 111.3 (CH), 111.5 (2×CH), dd, J_(CF)=18.4 and 7.0 Hz), 124.2 (CH),127.5 (C), 134.5 (C), 137.4 (C), 143.0 (C, t, J_(CF)=9.2 Hz), 149.4 (C),163.2 (2×, dd, J_(CF)=247.0 and 13.9 Hz). HRMS (ES) calcd. forC₁₇H₁₉F₂N₂O₄S (MH⁺), 385.1028 found 385.1013. HPLC t_(r)=1.20 min(98.8%), (CH₃CN/H₂O 90/10)

Synthesis of 4-functionalised 1,2,3,4-tetrahydroisoquinoline derivativesN-(2,2-Diethoxyethyl)-4-benzyloxy-3-methoxybenzylamine F8

4-Benzyloxy-3-methoxybenzaldehyde (50 g, 206 mmol) and aminoacetaldehyde diethyl acetal (31.6 mL, 217 mmol) were heated up to 65° C.for 6 hours then cooled to rt. The resulting yellow oil was stirred inethanol (250 mL), cooled to 0° C. and NaBH₄ (8.3 g, 220 mmol) was addedportion wise. The mixture was refluxed for 4 hours then cooled to 0° C.and water added. The solution was stirred for 30 minutes, extracted withethyl acetate and the organic layer was washed with water, brine, driedand concentrated to yield 72 g (97%) of a yellow oil, ¹H NMR (270 MHz,CDCl₃) δ 1.19 (6H, t, J=7.2 Hz), 1.51 (1H, br s), 2.72 (2H, d, J=5.5Hz), 3.51 (2H, dq, J=7.2 and 1.9 Hz), 3.67 (2H, dq, J=7.2 and 1.9 Hz),3.72 (2H, s), 3.88 (3H, s), 4.60 (1H, t, J=5.5 Hz), 5.13 (2H, s), 6.75(1H,dd, J=8.3 and 1.4 Hz), 6.81 (1H, d, J=8.3 Hz), 6.89 (1H, d, J=1.4Hz), 7.27-7.44 (5H, m). HRMS (ES) calcd. for C₂₁H₃₀NO₄ (MH⁺), 360.2169found 360.2161; HPLC: tr=3.92 (99.2%) CH₃CN/H₂O 90/10.

6-Benzyloxy-7-methoxy-1,2,3,4-tetrahydro-isoquinolin-4-ol F9 Asuspension of F8 (30 g, 83.5 mmol) in dioxane (40 mL) and 6M HCl (500mL) was stirred at 40° C.: The initial suspension dissolved and aprecipitate appeared after approximately 30 minutes. The mixture wasstirred for an additional 30 minutes: and the reaction mixture wascooled to 0° C. The white precipitate was collected by filtration,washed with water, diethyl ether, resuspended in water (300 mL) and themixture made alkaline with 5M aqueous sodium hydroxide. The whitesuspension was collected by filtration, washed with water, diethyl etherand dried under vacuum (17 g, 71%). m.p. 148-149° C., ¹H NMR (270 MHz,CDCl₃) δ 2.33 (2H, br), 2.94 (1H, dd, J=13.0 and 2.8 Hz), 2.94 (1H, dd,J=13.0 and 2.8 Hz), 3.79 (1H, d, J=2.2 Hz), 3.84 (3H, s), 4.39 (1H, t,J=2.8 Hz), 5.12 (2H, s), 6.4 (1H, s), 6.89 (1H, s), 7.27-7.44 (5H, m).HRMS (ES) calcd. for C₁₇H₂₀NO₃ (MH⁺), 286.1438 found 286.1425. HPLC:tr=4.70 (99.7%) CH₃CN/H₂O 90/10.2-tert-Butoxycarbonyl-6-benzyloxy-7-methoxy-3,4-dihydro-1H-isoquinoline-4-olF10

A solution of F9 (14.2 g, 49.8 mmol) Boc₂O (13.1 g, 60 mmol) in THF (150mL) was refluxed for 6 hours. The suspension was then cooled to 0° C.filtered, washed with ice cold THF and dried under vacuum, affording18.3 g (95%) of a white solid. m.p. 196-197° C., ¹H NMR (270 MHz, CDCl₃)δ 1.48 (9H, s), 3.48 (1H, dd, J=13.5 and 3.3 Hz), 3.86 (3H, s), 3.92(1H, dd, J=13.5 and 4.4 Hz), 4.30 (1H, d, J=16.8 Hz), 4.59 (1H, br),4.69 (1H, d, J=16.8 Hz), 5.09 (1H, d, J=12.1 Hz), 5.16 (1H, d, J=12.1Hz), 6.60 (1H, s), 6.96 (1H, s), 7.28-7.44 (5H, m). HRMS (ES) calcd. forC₂₂H₂₇NO₅Na (M+Na⁺), 408.1781 found 408.1782; HPLC: tr=1.95 (100%)CH₃CN/H₂O 90/10.

2-tert-Butoxycarbonyl-6-benzyloxy-4,7-dimethoxy-3,4-dihydro-1H-isoquinolin-4-olF11

A suspension of F10 (5.8 g, 15 mmol) in dry THF (50 mL) and DMF (10 mL)was cooled to 0° C. and treated with 60% NaH (0.8 g, 20 mmol in aportion wise manner. The mixture was stirred for 30 minutes at 0° C.before methyl iodide (1.25 mL, 20 mmol) was added and the mixturestirred at rt for 16 hours. After careful addition of water, the mixturewas extracted with ethyl acetate, the combined organic layers washedwith water, brine, dried and evaporated. The resulting yellow oil (6.5g) was purified by flash chromatography (hexane/EtOAc 20/1 to 3/1) toafford a white solid (5.7 g, 95%), m.p. 86-88° C., ¹H NMR (270 MHz,CDCl₃) δ 1.48 (9H, s), 3.38 (3H, s), 3.33-3.52(1H, m), 3.85 (3H, s),3.94-4.18 (2H, m), 4.28-4.40 (1H, m), 4.58-4.76 (1H, m), 5.10 (1H, d,J=12.1 Hz), 5.15 (1H, d, J=12.1 Hz), 6.61 (1H, s), 6.86 and 690 (1H, s),7.28-7.45 (5H, m). HRMS (ES) calcd. for C₂₃H₂₉NO₅Na (M+Na⁺), 422.1938found 422.1927. HPLC: tr=2.40 (100%) CH₃CN/H₂O 90/10.

6-Benzyloxy-4,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline F12

F11 (5.4 g, 13.5 mmol) was stirred in THF (80 mL) and methanol (10 mL)and cooled to 0° C. before acetyl chloride (5.8 mL, 80 mmol) was addeddrop wise. The solution was stirred at rt o/n, After addition of DCM(100 mL), the organic layer was successively washed with saturatedaqueous NaHCO₃, water and brine, dried (MgSO₄), filtered andconcentrated to afford 4.2 g of a crude dark yellow solid. Columnchromatography (petroleum ether/ethyl acetate 9/1 to 0/1 then ethylacetate/methanol 1/0 to 10/1) afforded 1.8 g (45%) of6-Benzyloxy-4,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline F12 and6-benzyloxy-7-methoxyisoquinoline F13 (400 mg, 11%);

F12 white powder, m.p. 108-109° C., ¹H NMR (270 MHz, CDCl₃) δ 1.95 (1H,br), 2.90 (1H, dd, J=13.8 and 2.8 Hz), 3.33 (3H, s), 3.35 (1H, dd,J=13.8 and 5.9 Hz), 3.84 (3H, s), 3.87-3.96 (3H, m), 5.13 (2H, s), 6.54(1H, s), 6.80 (1H, s), 7.28-7.45 (5H, m). HRMS (ES) calcd. for C₁₈H₂₂NO₃(MH⁺), 300.1594 found 300.1584. HPLC: tr=4.32 (97.2%) CH₃CN/H₂O 90/10

F13 cream colour powder, m.p. 138-139° C., ¹H NMR (270 MHz, CDCl₃) δ4.02 (3H, s), 5.29 (2H, s), 7.09 (1H, s), 7.21 (1H, s), 7.29-7.50 (6H,m), 8.35 (1H, d, J=5.8 Hz), 9.03 (1H, s); HRMS (ES) calcd. for C₁₇H₁₆NO₂(MH⁺), 266.1176 found 266.1165. HPLC: tr=2.70 (99.2%) CH₃CN/H₂O 90/10

2-tert-Butoxycarbonyl-4-ethoxy-6-benzyloxy-7-methoxy-3,4-dihydro-1H-isoquinolineF14

A suspension of F10 (5.8 g, 15 mmol) in dry THF (50 mL) and dry DMF (10mL) was cooled to 0° C. and treated with 60% NaH (0.8 g, 20 mmol) in aportion wise manner. The reaction mixture was stirred for 30 minutes at0° C. before ethyl iodide (1.6 mL, 20 mmol) was added and the mixturestirred at rt for 16 hours. After careful addition of water, the mixturewas extracted with ethyl acetate, the organic layers separated, washedwith water, brine, dried (MgSO₄), filtered and concentrated. Theresulting yellow oil (6.5 g) was purified by flash chromatography(hexane/EtOAc 20/1 to 3/1) to afford F14 as a white solid (4.7 g, 76%),m.p. 85-86° C., ¹H NMR (270 MHz, CDCl₃) δ 1.19 (3H, t, J=6.9 Hz), 1.47(9H, s), 3.37-3.71(3H, m), 3.85 (3H, s), 3.88-4.00 (1H, m), 4.22-4.42(2H, m), 4.55-4.73 (1H, m), 5.13 (2H, s), 6.60 (1H, s), 6.85 and 690(1H, s), 7.27-7.45 (5H, m). HRMS (ES) calcd. for C₂₄H₃₁NNaO₅ (M+Na⁺),436.2094 found 436.2095. HPLC: tr=2.74 (99.3%) CH₃CN/H₂O 90/10.

6-Benzyloxy-4-ethoxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline F15

6-Benzyloxy-4-ethoxy-7-methoxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.7 g, 11.4 mmol) was stirred in THF (50 mL) andmethanol (5 mL) and cooled to 0° C. before acetyl chloride (2 mL, 28mmol) was added drop wise. The solution was stirred at rt for an o/n.After addition of DCM (100 mL) the organic layer was washed with asolution of saturated aqueous NaHCO₃, water, brine, dried (MgSO₄),filtered and concentrated to afford 3.6 g of crude product. Columnchromatography (petroleum ether/ethyl acetate 9/1 to 0/1 then ethylacetate/methanol 1/0 to 10/1) afford 1.5 g (42%) of6-Benzyloxy-4-ethoxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline F15 and6-benzyloxy-7-methoxyisoquinoline F16 (0.7 g, 23%). F15 white powder,m.p. 55-56° C., ¹H NMR (270 MHz, CDCl₃) δ 1.16 (3H, t, J=6.9 Hz), 2.10(1H, br), 2.91 (1H, dd, J=13.8 and 2.8 Hz), 3.29 (1H, dd, J=13.8 and 2.5Hz), 3.37-3.61 (2H, m), 3.84 (3H, s), 3.87-3.95 (2H, m), 4.00-4.06 (1H,m), 5.14 (2H, s), 6.53 (1H, s), 6.78 (1H, s), 7.26-7.44 (5H, m). HRMS(ES) calcd. for C₁₉H₂₄NO₃ (MH⁺), 314.1751 found 314.1744. HPLC: tr=4.16(95.8%) CH₃CN/H₂O 90/10.

For N-benzylations see Method 1 for the “Synthesis of6-(benzyloxy)-2-benzyl-1,2,3,4-tetrahydroisoquinolines”

6-Benzyloxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-4-olF17

480 mg (79%), white powder, m.p. 115-116° C., ¹H NMR (270 MHz, CDCl₃) δ2.60 (1H, dd, J=11.6 and 2.9 Hz), 2.66 (1H, br), 3.04 (1H, dd, J=11.6and 2.8 Hz), 3.28 (1H, d, J=14.9 Hz), 3.62-3.75 (3H, m), 3.80 (3H, s),3.81 (3H, s), 4.47 (1H, br), 5.08 (H, d, J=12.1 Hz), 5.16 (H, d, J=12.1Hz), 6.50 (1H, s), 6.80-6.84 (1H, m), 6.93-6.96 (3H, m), 7.25 (1H, t,J=7.7 Hz), 7.29-7.44 (5H, m); ¹³C NMR (100 MHz, CDCl₃) δ 55.2 (CH₃),55.4 (CH₂), 56.0 (CH₃), 58.4 (CH₂), 62.6 (CH₂), 67.1 (C), 70.9 (CH₂),109.1 (CH), 112.7 (CH), 114.1 (CH), 114.5 (CH), 121.3 (CH), 127.3(2×CH), 127.7 (C), 127.8 (CH), 128.5 (2×CH), 128.7 (C), 129.4 (CH),137.0 (C), 139.5 (C), 147.1 (C), 149.3 (C) and 159.7 (C). HRMS (ES)calcd. for C₂₅H₂₈NO₄ (MH⁺), 406.2013 found 406.1997. HPLC: tr=2.13(99.5%) CH₃CN/H₂O 90/10.

6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquino-lin-4-olF18

450 mg, (64%), white powder, m.p.: 126-127° C., ¹H NMR (270 MHz, CDCl₃)δ 2.53 (1H, dd, J=11.9 and 2.8 Hz), 3.04 (1H, d, J=10.7 Hz), 3.03 (1H,dd, J=11.9 and 2.8 Hz), 3.31 (1H, d, J=14.9 Hz), 3.63 (2H, s), 3.74 (1H,d, J=14.9 Hz), 3.83 (3H, s), 3.84 (9H, s), 4.48 (1H, dt, 10.7 and 2.8Hz), 5.09 (1H, d, J=12.2 Hz), 5.16 (1H, d, J=12.2 Hz), 6.53 (1H, s),6.59 (2H, s), 6.94 (1H, s), 7.28-7.45 (5H, m); ¹³C NMR (100 MHz, CDCl₃)δ 55.7 (CH₂), 56.0 (CH₃), 56.1 (2×CH₃), 58.2 (CH₂), 60.9 (CH₃), 62.8(CH₂), 67.1 (CH), 71.0 (CH₂), 105.5 (2×CH), 109.2 (CH), 114.0 (CH),127.3 (2×CH), 127.7 (C), 127.8 (CH), 128.5 (2×CH), 128.7 (C), 133.7 (C),137.0 (C), 147.1 (C), 149.4 (C) and 153.2 (2×C). HRMS (ES) calcd. forC₂₇H₃₂NO₆ (MH⁺), 466.2224 found 466.2210. HPLC: tr=1.92 (98%) CH₃CN/H₂O90/10.

6-Benzyloxy-4,7-dimethoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF19

465 mg, (74%), light yellow powder, m.p.: 101-102° C., ¹H NMR (270 MHz,CDCl₃) δ 2.78 (1H, dd, J=11.8 and 4.1 Hz), 2.91 (1H, dd, J=11.8 and 5.1Hz), 3.34 (3H, s), 3.49 (1H, d, J=14.6 Hz), 3.68 (1H, d, J=14.6 Hz),3.75 (2H, s), 3.82 (3H, s), 3.84 (3H, s), 4.31 (1H, dd, J=5.1 and 4.1Hz), 5.08 (1H, d, J=12.1 Hz), 5.14 (1H, d, J=12.1 Hz), 6.53 (1H, s),6.88 (1H, d, J=8.2 Hz), 6.91-6.97 (2H, m), 7.20-7.49 (7H, m); ¹³C NMR(100 MHz, CDCl₃) δ 54.1 (CH₂), 55.4 (CH₃), 55.5 (CH₂), 55.7 (CH₂), 56.0(2×CH₃), 71.0 (CH₂), 75.2 (CH), 109.2 (CH), 110.3 (CH), 114.0 (CH),120.4 (CH), 126.0 (C), 126.4 (C), 127.4 (2×CH), 127.7 (CH), 128.0 (CH),128.5 (2×CH), 129.0 (C), 130.3 (CH), 137.2 (C), 146.8 (C), 149.2 (C) and157.7 (C). HRMS (ES) calcd. for C₂₆H₃₀NO₄ (MH⁺), 420.2169 found420.2166. HPLC: tr=3.24 (94.0%) CH₃CN/H₂O 90/10

6-Benzyloxy-4,7-dimethoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF20

490 mg (77%), light yellow powder, m.p.: 96-97° C., ¹H NMR (270 MHz,CDCl₃) δ 2.70 (1H, dd, J=11.8 and 4.1 Hz), 2.89 (1H, dd, J=11.8 and 4.7Hz), 3.31 (3H, s), 3.44 (1H, d, J=14.6 Hz), 3.59 (1H, d, J=13.2 Hz),3.66 (1H, d, J=14.6 Hz), 3.76 (1H, d, J=13.2 Hz), 3.80 (3H, s), 3.81(3H, s), 4.30 (1H, dd, J=4.7 and 4.1 Hz), 5.09 (1H, d, 12.4 Hz), 5.15(1H, d, J=12.4 Hz), 6.53 (1H, s), 6.80-6.84 (1H, m), 6.94 (1H, s),6.96-6.99 (2H, m), 7.24 (1H, t, J=8.3 Hz), 7.26-7.45 (5H, m); ¹³C NMR(100 MHz, CDCl₃) δ 53.9 (CH₂), 55.2 (CH₃), 55.7 (CH₂), 56.0 (CH₃), 62.5(CH₂), 71.0 (CH₂), 75.1 (CH), 109.2 (CH), 112.9 (CH), 114.1 (CH), 114.2(CH), 121.3 (CH), 126.3 (C), 127.4 (2×CH), 127.7 (CH), 128.4 (2×CH),128.7 (C), 129.2 (CH), 137.2 (C), 139.7 (C), 146.9 (C), 149.3 (C) and159.7 (C). HRMS (ES) calcd. for C₂₆H₃₀NO₄ (MH⁺), 420.2169 found420.2152. HPLC: tr=2.60 (100%) CH₃CN/H₂O 90/10.

6-Benzyloxy)-4,7-dimethoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF21

500 mg (80%), light yellow powder, ¹H NMR (400 MHz, CDCl₃) δ 2.71 (2H,dd, J=11.7 and 3.9 Hz), 2.87 (2H, dd, J=11.7 and 5.1 Hz), 3.31 (3H, s),3.42 (1H, d, J=14.5 Hz), 3.47 (1H, d, J=12.9 Hz),3.64 (1H, d, J=14.5Hz), 3.72 (1H, d, J=12.9 Hz),3.80 (3H, s), 3.81 (3H, s), 4.29 (1H, dd,J=5.1 and 3.9 Hz), 5.10 (1H, d, J=12.2 Hz), 5.15 (1H, d, J=12.2 Hz),6.53 (1H, s), 6.86-6.89 (2H, m), 6.94 (1H, s), 7.26-7.38 (5H, m),7.42-7.45 (2H, m); ¹³C NMR (100 MHz, CDCl₃) δ 53.7 (CH₂), 55.1 (CH₃),55.6 (CH₂), 55.9 (2×CH₃), 61.9 (CH₂), 71.0 (CH₂), 75.1 (CH), 109.2 (CH),113.6 (2×CH), 114.1 (CH), 126.3 (C), 127.4 (2×CH), 127.7 (CH), 128.4(2×CH), 128.7 (C), 130.2 (2×CH), 137.1 (C), 146.8 (C), 149.3 (C) and158.7 (C). HRMS (ES) calcd. for C₂₆H₃₀NO₄ (MH⁺), 420.2169 found420.2157. HPLC: tr=3.11 (95.2%) CH₃CN/H₂O 90/10.

6-Benzyloxy-4,7-dimethoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF22

490 mg (68%), white powder, m.p. 89-90° C., ¹H NMR (400 MHz, CDCl₃) δ2.64 (1H, dd, J=11.8 and 3.9 Hz), 2.91 (1H, dd, J=11.8 and 4.3 Hz), 3.32(3H, s), 3.45 (1H, d, J=14.5 Hz), 3.51 (1H, d, J=13.3 Hz), 3.70 (1H, d,J=14.5 Hz), 3.76 (1H, d, J=13.3 Hz), 3.83 (3H, s), 3.84 (3H, s), 3.85(6H, s), 4.27 (1H, dd, J=4.3 and 3.9 Hz), 5.10 (1H, d, J=12.0 Hz), 5.14(1H, d, J=12.0 Hz), 6.55 (1H, s), 6.55 (2H, s), 6.93 (1H, s), 7.27-7.30(1H, m), 7.33-7.37 (2H, m), 7.43 (2H, d, J=7.0 Hz); ¹³C NMR (100 MHz,CDCl₃) δ 53.5 (CH₂), 56.0 (CH₂), 56.0 (CH₃), 56.1 (2×CH₃), 60.9 (CH₃),60.9 (CH₃), 62.7 (CH₂), 71.1 (CH₂), 75.2 (CH), 105.5 (2×CH), 109.3 (CH),114.2 (CH), 126.3 (C), 127.4 (2×CH), 127.7 (CH), 128.4 (2×CH), 128.6(C), 134.0 (C), 136.9 (C), 137.1 (C), 147.0 (C), 149.4 (C) and 153.2(2×C). HRMS (Electrospray) calcd. for C₂₈H₃₄NO₆ (MH⁺), 480.2381 found480.2363. HPLC: tr=2.74 (95.3%) CH₃CN/H₂O 90/10.

6-Benzyloxy-4-ethoxy-7-methoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF23

395 mg (61%), yellow oil, ¹H NMR (270 MHz, CDCl₃) δ 1.19 (3H, t, J=6.9Hz), 2.83 (1H, d, J=4.9 Hz), 3.48-3.58 (3H, m), 3.66 (1H, d, J=14.3 Hz),3.74 (2H, s), 3.81 (3H, s), 3.82 (3H, s), 4.41 (1H, t, J=4.9 Hz), 5.13(2H, s), 6.52 (1H, s), 6.86-6.97 (3H, m), 7.20-7.51 (7H, m), ¹³C NMR(100 MHz, CDCl₃) δ 15.6 (CH₃), 54.8 (CH₂), 55.2 (CH₃), 55.4 (CH₂), 55.7(CH₂), 55.9 (CH₃), 63.7 (CH₂), 71.0 (CH₂), 73.8 (CH), 109.1 (CH), 110.2(CH), 113.9 (CH), 120.2 (CH), 126.1 (C), 127.0 (C), 127.2 (2×CH), 127.6(CH), 127.8 (CH), 128.3 (2×CH), 128.8 (C), 130.0 (CH), 137.2 (C), 146.8(C), 149.1 (C) and 157.6 (C). HRMS (ES) calcd. for C₂₇H₃₂NO₄ (MH⁺),434.2326 found 434.2335. HPLC: tr=3.64 (95.2%) CH₃CN/H₂O 90/10.

6-Benzyloxy-4-ethoxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF24

405 mg (62%), yellow oil, ¹H NMR (270 MHz, CDCl₃) δ 1.16 (3H, t, J=6.9Hz), 2.78 (2H, d, J=5.0 Hz), 3.44-3.63 (5H, m), 3.74 (1H, d, J=13.2 Hz),3.80 (3H, s), 3.82 (3H, s), 4.40 (1H, t, J=5.0 Hz), 5.14 (2H, s), 6.51(1H, s), 6.81 (1H, dd, J=8.0 and 2.5 Hz), 6.94 (1H, s), 6.96-6.99 (2H,m), 7.21-7.46 (6H, m); ¹³C NMR (100 MHz, CDCl₃) δ 15.7 (CH₃), 54.7(CH₂), 55.2 (CH₃), 55.8 (CH₂), 56.0 (CH₃), 62.5 (CH₂), 63.8 (CH₂), 71.1(CH₂), 73.8 (CH), 109.1 (CH), 112.7 (CH), 113.9 (CH), 114.2 (CH), 121.3(CH), 127.0 (C), 127.3 (2×CH), 127.7 (CH), 128.4 (2×CH), 128.5 (C),129.2 (CH), 137.3 (C), 139.8 (C), 146.9 (C), 149.2 (C) and 159.7 (C).HRMS (ES) calcd. for C₂₇H₃₂NO₄ (MH⁺), 434.2326 found 434.2331. HPLC:tr=3.11 (94.8%) CH₃CN/H₂O 90/10.

6-Benzyloxy-4-ethoxy-7-methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF25

435 mg (67%), yellow powder, m.p. 84-85° C., ¹H NMR (270 MHz, CDCl₃) δ1.15 (3H, t, J=7.2 Hz), 2.68-2.80 (2H, m), 3.40-3.59 (5H, m), 3.69 (1H,d, J=12.9 Hz), 3.80 (3H, s), 3.81 (3H, s), 4.38 (1H, dd, J=5.2 and 4.7Hz), 5.12 (2H, s), 6.49 (1H, s), 6.6.85 (2H, d, =8.5 Hz), 6.92 (1H, s),7.26-7.39 (5H, m), 7.42 (2H, d, J=8.5 Hz); ¹³C NMR (100 MHz, CDCl₃) δ15.7 (CH₃), 54.6 (CH₂), 55.2 (CH₃), 55.7 (CH₂), 56.0 (CH₃), 61.9 (CH₂),63.8 (CH₂), 71.1 (CH₂), 73.8 (CH), 109.1 (CH), 109.2 (CH), 113.6 (2×CH),114.0 (CH), 127.1 (C), 127.3 (2×CH), 127.7 (CH), 128.4 (2×CH), 128.6(C), 130.1 (2×CH), 137.3 (C), 146.9 (C), 149.2 (C) and 158.7 (C). HRMS(ES) calcd. for C₂₇H₃₂NO₄ (MH⁺), 434.2326 found 434.2314. HPLC: tr=3.64(97.8%) CH₃CN/H₂O 90/10.

6-Benzyloxy-4-ethoxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydro-isoquinolineF26

385 mg (52%), light yellow powder, m.p. 132-133° C., ¹H NMR (270 MHz,CDCl₃) δ 1.14 (3H, t, J=6.9 Hz), 2.71 (1H, dd, J=11.6 and 4.4 Hz), 2.79(1H, dd, J=11.6 and 5.2 Hz), 3.41-3.74 (6H, m), 3.83 (3H, s), 3.84 (9H,s), 4.38 (1H, dd, J=5.2 and 4.4 Hz), 5.13 (2H, s), 6.53 (1H, s), 6.63(2H, s), 6.92 (1H, s), 7.27-7.44 (5H, m), ¹³C NMR (100 MHz, CDCl₃) δ15.7 (CH₃), 54.6 (CH₂), 55.9 (CH₂), 56.0 (CH₃), 56.1 (2×CH₃), 60.9(CH₃), 62.8 (CH₂), 63.9 (CH₂), 71.1 (CH₂), 73.8 (CH), 105.5 (2×CH),109.2 (CH), 114.0 (CH), 126.9 (C), 127.3 (2×CH), 127.7 (CH), 128.5(2×CH), 134.0 (C), 137.3 (C), 147.0 (C), 149.3 (C) and 153.2 (2×C). HRMS(ES) calcd. for C₂₉H₃₆NO₆ (MH⁺), 494.2537 found 494.2523. HPLC: tr=2.54(99.0%) CH₃CN/H₂O 90/10.

4-O-Acetyl-6-benzyloxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF27

A solution of F17 (330 mg, 0.81 mmol) in DCM (20 mL) and TEA (0.14 mL,0.9 mmol) was cooled to 0° C. before Ac₂O (0.085 mL, 0.9 mL) was addeddropwise. The mixture was stirred at rt o/n. After addition of water (50mL), the organics were extracted with DCM and the organic layer washedwith aq. NaHCO₃ water, brine, dried (MgSO₄), filtered and concentrated.The crude oil (0.5 g) was purified by flash chromatography to give ayellow powder (340 mg, 94%), m.p.: 96-97° C., ¹H NMR (270 MHz, CDCl₃) δ2.01 (3H, s), 2.65 (1H, dd, J=12.7 and 3.6 Hz), 2.97 (1H, dd, J=12.7 and3.3 Hz), 3.39 (1H, d, J=14.6 Hz), 3.59 (1H, d, J=13.2 Hz), 3.75-3.83(8H, m), 5.07 (H, d, J=12.4 Hz), 5.14 (H, d, J=12.4 Hz), 5.85 (1H, dd,J=3.6 and 3.3 Hz), 6.54 (1H, s), 6.79 (1H, d, J=2.2 Hz), 6.82 (1H, s),6.94-6.97 (2H, m), 7.20-7.42 (6H, m); ¹³C NMR (100 MHz, CDCl₃) δ 21.3(CH₃), 54.8 (CH₂), 55.1 (CH₃), 55.3 (CH₂), 55.9 (CH₃), 62.0 (CH₂), 68.5(CH), 70.8 (CH₂), 109.2 (CH), 112.5 (CH), 114.3 (CH), 114.5 (CH), 121.3(CH), 123.9 (C), 127.3 (2×CH), 127.7 (CH), 128.4 (2×CH), 129.1 (C),129.2 (CH), 136.9 (C), 139.2 (C), 146.8 (C), 149.8 (C), 159.6 (C) and171.0 (CO). HRMS (ES) calcd. for C₂₇H₃₀NO₅ (MH⁺), 448.2118 found448.2104. HPLC: tr=2.41 (97.7%) CH₃CN/H₂O 90/10.

Deprotections of the O-benzyl group: see Method 1 of the “Synthesis of6-hydroxy-2-benzyl-1,2,3,4-tetrahydroisoquinolines”

7-Methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline-4,6-diolF28

240 mg (75%), yellow powder, m.p. 137-138° C., ¹H NMR (400 MHz, CDCl₃) δ2.63 (1H, dd, J=11.5 and 2.3 Hz), 3.07 (1H, dd, J=11.5 and 2.0 Hz), 3.29(1H, d, J=14.5 Hz), 3.66 (1H, d, 14.5 Hz), 3.70 (1H, d, 13.3 Hz), 3.73(1H, d, 13.3 Hz), 3.81 (3H, s), 3.82 (3H, s), 4.51 (1H, dd, J=2.4 and2.0 Hz), 6.47 (1H, s), 6.81-6.85 (1H, m), 6.94-6.97 (3H, m), 7.25 (1H,t, J=7.8 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 55.2 (CH₃), 55.5 (CH₂), 55.9(CH₃), 58.5 (CH₂), 62.6 (CH₂), 66.9 (CH), 108.1 (CH), 112.8 (CH), 114.5(CH), 114.7 (CH), 121.4 (CH), 126.4 (C), 129.4 (CH), 129.6 (C), 144.5(C), 146.4 (C) and 159.7 (C). HRMS (ES) calcd. for C₁₈H₂₂NO₄ (MH⁺),316.1543 found 316.1534. HPLC: tr=1.62 (99.2%) CH₃CN/H₂O 90/10.

7-Methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline-4,6-diolF29

325 mg (87%), yellow powder, m.p. 62-63° C., ¹H NMR (270 MHz, CDCl₃) δ2.59 (1H, dd, J=11.8 and 2.8 Hz), 2.65 (1H, br), 3.05 (1H, dd, J=11.8and 2.8 Hz), 3.29 (1H, d, J=14.3 Hz), 3.63 (2H, s), 3.73 (1H, d, J=14.3Hz), 3.83 (3H, s), 3.84 (9H, s), 4.52 (1H, br s), 5.59 (1H, br s), 6.48(1H, s), 6.59 (2H, s), 6.95 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 55.7(CH₂), 55.9 (CH₃), 56.1 (2×CH₃), 58.3 (CH₂), 60.9 (CH₃), 62.8 (CH₂),66.9 (CH), 105.6 (2×CH), 108.1 (CH), 114.7 (CH), 126.5 (C), 129.5 (C),133.7 (C), 137.0 (C), 144.5 (C), 146.4 (C) and 153.2 (2×C). HRMS (ES)calcd. for C₂₀H₂₆NO₆ (MH⁺), 376.1755 found 376.1745. HPLC: tr=1.92 (98%)CH₃CN/H₂O 90/10.

4,7-Dimethoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydro-isoquinolin-6-olF30

285 mg (86%), yellow powder, m.p. 45-47° C., ¹H NMR (270 MHz, CDCl₃) δ2.76 (1H, dd, J=11.8 and 3.8 Hz), 2.93 (1H, dd, J=11.8 and 4.9 Hz), 3.41(3H, s), 3.48 (1H, d, J=14.4 Hz), 3.68 (1H, d, J=14.4 Hz), 3.76 (2H, s),3.82 (3H, s), 3.84 (3H, s), 4.31 (1H, dd, J=4.9 and 3.8 Hz), 5.50 (1H,br), 6.48 (1H, s), 6.88 (1H, d, J=8.3 Hz), 6.93 (1H, t, J=7.4 Hz), 6.94(1H, s), 7.24 (1H, dd, J=7.4 and 1.4 Hz), 7.48 (1H, dd, J=7.4 and 1.4Hz); ¹³C NMR (100 MHz, CDCl₃) δ 54.2 (CH₂), 55.4 (CH₃), 55.5 (CH₂), 55.7(CH₂), 55.9 (CH₃), 56.3 (CH₃), 75.2 (CH₂), 108.1 (CH), 110.3 (CH), 114.3(CH), 120.4 (CH), 126.0 (C), 127.3 (C), 127.6 (C), 128.0 (CH), 130.4(CH), 144.2 (C), 146.2 (C) and 157.8 (C). HRMS (ES) calcd. for C₁₉H₂₄NO₄(MH⁺), 330.1700 found 330.1684. HPLC: tr=2.20 (98.7%) CH₃CN/H₂O 90/10.

4,7-Dimethoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydro-isoquinolin-6-olF31

220 mg (67%), yellow powder, m.p. 133-134° C., ¹H NMR (400 MHz, CDCl₃) δ2.72 (1H, dd, J=11.8 and 4.0 Hz), 2.90 (1H, dd, J=11.8 and 4.7 Hz), 3.38(3H, s), 3.44 (1H, d, J=14.6 Hz), 3.61 (1H, d, J=13.5 Hz), 3.65 (1H, d,J=14.6 Hz), 3.77 (1H, d, J=13.5 Hz), 3.81 (3H, s), 3.82 (3H, s), 4.30(1H, app. t, J=4.3 Hz), 5.50 (1H, br), 6.48 (1H, s), 6.81 (1H, dd, J=7.8and 2.4 Hz), 6.95 (1H, s), 6.96-7.00 (2H, m), 7.24 (1H, t, J=7.8 Hz);¹³C NMR (100 MHz, CDCl₃) δ 54.0 (CH₂), 55.2 (CH₃), 55.7 (CH₂), 55.9(CH₃), 56.3 (CH₂), 62.5 (CH₂), 75.1 (CH), 108.3 (CH), 112.9 (CH), 114.2(CH), 114.4 (CH), 121.4 (CH), 127.2 (C), 129.2 (CH), 137.2 (C), 139.7(C), 144.3 (C), 146.3 (C) and 159.7 (C). HRMS (ES) calcd. for C₁₉H₂₄NO₄(MH⁺), 330.1700 found 330.1694. HPLC: tr=1.07 (99.2%) CH₃CN/H₂O 90/10.

4,7-Dimethoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydro-isoquinolin-6-olF32

200 mg (62%), yellow powder, m.p. 84-85° C., ¹H NMR (400 MHz, CDCl₃) δ2.69 (1H, dd, J=11.8 and 4.1 Hz), 2.87 (1H, dd, J=11.8 and 4.9 Hz), 3.36(3H, s), 3.40 (1H, d, J=14.6 Hz), 3.57 (1H, d, J=13.0 Hz),3.62 (1H, d,J=14.6 Hz), 3.71 (1H, d, J=13.0 Hz), 3.79 (3H, s), 3.80 (3H, s), 4.28(1H, app. t, J=4.4 Hz), 5.52 (1H, br), 6.46 (1H, s), 6.86 (2H, d, J=8.5Hz), 6.93 (1H, s), 7.30 (2H, d, J=8.5 Hz); ¹³C NMR (100 MHz, CDCl₃) δ54.0 (CH₂), 55.3 (CH₃), 55.7 (CH₂), 56.0 (CH₃), 56.4 (CH₃), 62.0 (CH₂),75.2 (CH), 108.2 (CH), 113.7 (2×CH), 114.5 (CH), 127.3 (C), 127.4 (C),130.0 (C), 130.4 (2×CH), 144.3 (C), 146.4 (C) and 158.9 (C). HRMS (ES)calcd. for C₁₉H₂₄NO₄ (MH⁺), 330.1700 found 330.1686. HPLC: tr=1.04(99.2%) CH₃CN/H₂O 90/10.

4,7-Dimethoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydro-isoquinolin-6-olF33

310 mg (80%), light yellow powder, m.p. 51-54° C., ¹H NMR (400 MHz,CDCl₃) δ 2.61 (1H, dd, J=11.8 and 3.6 Hz), 2.93 (1H, dd, J=11.8 and 4.4Hz), 3.39 (3H, s), 3.44 (1H, d, J=14.3 Hz), 3.50 (1H, d, J=13.2 Hz),3.69 (1H, d, J=14.3 Hz), 3.75 (1H, d, J=13.2 Hz), 3.83 (3H, s), 3.84(3H, s), 3.85 (6H, s), 4.27 (1H, app. t, J=4.1 Hz), 5.50 (1H, br), 6.50(1H, s), 6.65 (2H, s), 6.94 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 53.8(CH₂), 56.0 (CH₂), 56.1 (2×CH₃), 56.6 (CH₃), 61.0 (CH₃), 62.8 (CH₂),75.3 (CH), 105.6 (2×CH), 108.2 (CH), 114.6 (CH), 127.1 (C), 127.4 (C),127.4 (C), 128.5 (C), 134.1 (C), 144.4 (C), 146.5 (C) and 153.3 (2×C).HRMS (ES) calcd. for C₂₁H₂₈NO₆ (MH⁺), 390.1911 found 390.1893. HPLC:tr=1.04 (98.3%) CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-olF34

260 mg (75%), yellow powder, m.p. 101-102° C., ¹H NMR (270 MHz, CDCl₃) δ1.23 (3H, t, J=7.2 Hz), 2.83 (2H, d, J=5.0 Hz), 3.52 (1H, d, J=14.6 Hz),3.56-3.66 (3H, m), 3.74 (2H, s), 3.81 (3H, s), 3.83 (3H, s), 4.42 (1H,t, J=5.0 Hz), 5.42 (1H, br), 6.47 (1H, s), 6.87 (1H, d, J=8.3 Hz), 6.92(1H, d, J.=8.3 Hz), 7.20-7.26 (1H, m), 7.50 (1H, dd, J=7.4 and 1.6 Hz);¹³C NMR (100 MHz, CDCl₃) δ 15.8 (CH₃), 54.9 (CH₂), 55.5 (CH₂), 55.6(CH₃), 55.9 (CH₂), 56.0 (CH₃), 64.4 (CH₂), 74.0 (CH), 108.1 (CH), 110.4(CH), 114.2 (CH), 120.5 (CH), 126.3 (C), 127.6 (C), 128.0 (C), 128.1(CH), 130.3 (CH), 144.3 (C), 146.2 (C) and 157.8 (C). HRMS (ES) calcd.for C₂₀H₂₆NO₄ (MH⁺), 344.1856 found 344.1844. HPLC: tr=1.05 (97.5%)CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(3-methoxy-benzyl)-1,2,3,4-tetrahydroisoquinolin-6-olF35

250 mg (73%), yellow powder, m.p. 134-135° C., ¹H NMR (270 MHz, CDCl₃) δ1.22 (3H, t, J=6.9 Hz), 2.76 (1H, dd, J=12.2 and 5.2 Hz), 2.81 (1H, dd,J=12.2 and 4.9 Hz), 3.46 (1H, d, J=14.3 Hz), −3.53-3.62 (4H, m), 3.75(1H, d, J=13.2 Hz), 3.80 (3H, s), 3.81 (3H, s), 4.41 (1H, dd, J=5.2 and4.9 Hz), 5.49 (1H, br), 6.46 (1H, s), 6.80 (1H, dd, J=8.0 and 2.5 Hz),6.96-6.99 (3H, m), 7.23 (1H, t, J=8.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ15.7 (CH₃), 54.7 (CH₂), 55.2 (CH₃), 55.7 (CH₂), 55.9 (CH₃), 62.4 (CH₂),64.3 (CH₂), 73.7 (CH), 108.0 (CH), 112.9 (CH), 114.1 (CH), 114.2 (CH),121.4 (CH), 127.8 (C), 129.2 (CH), 144.3 (C), 146.2 (C), and 159.7 (C).HRMS (ES) calcd. for C₂₀H₂₆NO₄ (MH⁺), 344.1856 found 344.1841. HPLC:tr=1.79 (100%) CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-olF36

260 mg (75%), light yellow powder, m.p. 154-157° C., ¹H NMR (400 MHz,CDCl₃) δ 1.21 (3H, t, J=7.2 Hz), 2.75-2.80 (2H, m), 3.45 (1H, d, J=14.9Hz), 3.54-3.59 (4H, m), 3.71 (1H, d, J=12.9 Hz), 3.80 (3H, s), 3.81 (3H,s), 4.41 (1H, t, J=4.8 Hz), 5.48 (1H, br), 6.45 (1H, s), 6.86 (2H, d,=8.4 Hz), 6.96 (1H, s), 7.30 (2H, d, J=8.4 Hz); ¹³C NMR (100 MHz, CDCl₃)δ 15.7 (CH₃), 54.6 (CH₂), 55.2 (CH₃), 55.7 (CH₂), 55.9 (CH₃), 61.8(CH₂), 64.2 (CH₂), 73.8 (CH), 108.0 (CH), 113.6 (2×CH), 114.1 (CH),127.2 (C), 128.0 (C), 129.9 (C), 130.2 (2×CH), 144.3 (C), 146.1 (C) and158.8 (C). HRMS (ES) calcd. for C₂₀H₂₆NO₄ (MH⁺), 344.1856 found344.1840. HPLC: tr=1.00 (99.4%) CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-olF37

125 mg (31%), yellow powder, m.p. 94-96° C., ¹H NMR (270 MHz, CDCl₃) δ1.21 (3H, t, J=6.9 Hz), 2.74 (1H, dd, J=11.8 and 4.4 Hz), 2.80 (1H, dd,J=11.8 and 5.2 Hz), 3.46 (1H, d, J=15.1 Hz), 3.54-3.71 (4H, m), 3.73(1H, d, J=13.2 Hz), 3.82 (3H, s), 3.84 (9H, s), 4.40 (1H, dd, J=5.2 and4.4 Hz), 5.49 (1H, br), 6.48 (1H, s), 6.64 (2H, s), 6.96 (1H, s) ; ¹³CNMR (100 MHz, CDCl₃) δ 15.8 (CH₃), 54.8 (CH₂), 56.0 (CH₃), 56.1 (CH₂),56.2 (2×CH₃), 61.0 (CH₃), 62.9 (CH₂), 64.4 (CH₂), 73.9 (CH), 105.6(2×CH), 108.1 (CH), 114.2 (CH), 127.2 (C), 127.8 (C), 134.2 (C), 136.9(C), 144.4 (C), 146.3 (C) and 153.2 (2×C). HRMS (ES) calcd. forC₂₂H₃₀NO₆ (MH⁺), 404.2068 found 404.2054. HPLC: tr=2.03 (97.3%)CH₃CN/H₂O 90/10.

4-O-Acetyl-6-hydroxy-7-methoxy-2-(3-methoxy-benzyl)-1,2,3,4-tetrahydroisoquinolineF38

295 mg (82%), yellow powder, m.p. 44-46° C., ¹H NMR (270 MHz, CDCl₃) δ2.08 (3H, s), 2.69 (1H, dd, J=12.4 and 3.6 Hz), 2.96 (1H, dd, J=12.4 and3.3 Hz), 3.40 (1H, d, J=14.6 Hz), 3.59 (1H, d, J=13.5 Hz), 3.74 (1H, d,J=14.6 Hz), 3.77 (1H, d, J=13.5 Hz), 3.79 (3H, s), 3.83 (3H, s), 5.55(1H, br), 5.86 (1H, t, J=3.6 Hz), 6.51 (1H, s), 6.81 (1H, dd, J=8.0 and2.5 Hz), 6.85 (1H, s), 6.94-6.97 (2H, m), 7.23 (1H, t, J=8.0 Hz); ¹³CNMR (100 MHz, CDCl₃) δ 21.3 (CH₃), 54.9 (CH₂), 55.2 (CH₃), 55.3 (CH₂),55.9 (CH₃), 61.9 (CH₂), 68.5 (CH), 108.2 (CH), 112.6 (CH), 114.5 (CH),114.6 (CH), 121.3 (CH), 124.8 (C), 127.9 (C), 129.2 (CH), 139.2 (C),144.4 (C), 146.8 (C), 159.7 (C), and 171.0 (CO). HRMS (ES) calcd. forC₂₀H₂₄NO₅ (MR), 358.1649 found 358.1634. HPLC: tr=1.76 (99.1%) CH₃CN/H₂O90/10.

see “Synthesis of6-O-sulfamoyl-2-benzyl-1,2,3,4-tetrahydroisoquinolines”

4,7-Dimethoxy-6-O-sulfamoyl-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF39

175 mg (86%), yellow powder, m.p. 139-141° C., ¹H NMR (270 MHz, CDCl₃) δ2.74-2.82 (1H, m), 2.92 (1H, dd, J=11.8 and 4.9 Hz), 3.39 (3H, s), 3.52(1H, d, J=15.1 Hz), 3.72 (1H, d, J=15.1 Hz), 3.76 (2H, s), 3.80 (3H, d,J=3.3 Hz), 3.84 (3H, s), 4.31 (1H, m), 5.18 (2H, br), 6.62 (1H, s), 6.89(1H, d, J=8.3 Hz), 6.95 (1H, d, J=7.4 Hz), 6.94 (1H, s), 7.22-7.28 (1H,m), 7.35 (1H, d, J=3.3 Hz), 7.43 (1H, d, J=7.4 Hz); ¹³C NMR (100 MHz,CDCl₃) δ 53.8 (CH₂), 55.5 (CH₃), 55.6 (CH₂), 55.7 (CH₂), 56.3 (CH₃),56.6 (CH₃), 74.9 (CH₂), 110.5 (CH), 110.6 (CH), 120.6 (CH), 124.4 (CH),125.6 (C), 127.8 (C), 127.6 (C), 128.4 (CH), 130.6 (CH), 136.0 (C),137.7 (C), 150.9 (C) and 157.9 (C). HRMS (ES) calcd. for C₁₉H₂₅N₂O₆S(MH⁺), 409.1428 found 409.1412. HPLC: tr=1.80 (97.6%) CH₃CN/H₂O 90/10.

4,7-Dimethoxy-2-(3-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinolineF40

130 mg (64%), yellow powder, m.p. 142-144° C., ¹H NMR (270 MHz, CDCl₃) δ2.75 (1H, dd, J=11.8 and 4.1 Hz), 2.88 (1H, dd, J=11.8 and 4.9 Hz), 3.38(3H, s), 3.48 (1H, d, J=15.1 Hz), 3.61 (1H, d, J=13.2 Hz), 3.68 (1H, d,J=15.1 Hz), 3.77 (1H, d, J=13.2 Hz), 3.80 (3H, s), 3.82 (3H, s), 4.32(1H, dd, J=4.9 and 4.1 Hz), 5.08 (2H, br), 6.62 (1H, s), 6.81 (1H, dd,J=8.0 and 2.5 Hz), 6.94-6.97 (2H, m), 7.24 (1H, t, J=8.0 Hz), 7.37 (1H,s); ¹³C NMR (100 MHz, CDCl₃) δ 53.4 (CH₂), 55.3 (CH₃), 55.5 (CH₂), 56.3(CH₃), 56.6 (CH₃), 62.2 (CH₂), 74.6 (CH), 110.5 (CH), 113.2 (CH), 114.4(CH), 121.4 (CH), 122.9 (C), 124.3 (CH), 127.6 (C), 129.4 (CH), 132.2(C), 137.7 (C), 151.0 (C) and 159.8 (C). HRMS (ES) calcd. forC₁₉H₂₅N₂O₆S (MH⁺), 409.1428 found 409.1412. HPLC: tr=1.17 (99.7%)CH₃CN/H₂O 90/10

4,7-Dimethoxy-2-(4-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinolineF41

125 mg (61%), yellow powder, m.p.: 95-96° C., ¹H NMR (270 MHz, CDCl₃) δ2.73 (1H, dd, J=11.8 and 4.1 Hz), 2.88 (1H, dd, J=11.8 and 4.8 Hz), 3.35(3H, s), 3.46 (1H, d, J=15.1 Hz), 3.59 (1H, d, J=12.9 Hz), 3.67 (1H, d,J=15.1 Hz), 3.76 (1H, d, J=12.9 Hz), 3.79 (3H, s), 3.80 (3H, s),4.27-4.31 (1H, m), 5.30 (2H, br), 6.60 (1H, s), 6.86 (2H, d, J=8.5 Hz),7.27 (2H, d, J=8.5 Hz), 7.34 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 53.3(CH₂), 55.4 (CH₃), 55.5 (CH₂), 56.3 (CH₃), 56.6 (CH₃), 61.8 (CH₂), 74.7(CH), 110.5 (CH), 113.8 (2×CH), 124.4 (CH), 127.6 (C), 129.2 (CH), 130.42×CH), 135.4 (C), 137.7 (C), 151.0 (C) and 159.0 (C). HRMS (ES) calcd.for C₁₉H₂₅N₂O₆S (MH⁺), 409.1428 found 409.1418. HPLC: tr=1.11 (98.7%)CH₃CN/H₂O 90/10.

4,7-Dimethoxy-6-O-sulfamoyl-2-(3.4.5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolineF42

110 mg (47%), yellow powder, m.p. 125-126° C., ¹H NMR (400 MHz, CDCl₃) δ2.64 (1H, dd, J=11.8 and 3.6 Hz), 2.92 (1H, dd, J=11.8 and 4.5 Hz), 3.35(3H, s), 3.47 (1H, d, J=14.9 Hz), 3.51 (1H, d, J=13.2 Hz), 3.73 (1H, d,J=14.9 Hz), 3.76 (3H, s), 3.83 (3H, s), 3.81-3.83 (10H, m), 4.27 (1H,dd, J=4.4 and 3.6 Hz), 5.50 (2H, br), 6.61 (1H, s), 6.63 (2H, s), 7.31(1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 53.1 (CH₂), 55.9 (CH₂), 56.2(2×CH₃), 56.3 (CH₂), 56.7 (CH₃), 60.9 (CH₃), 62.5 (CH₂), 74.9 (CH),105.7 (2×CH), 110.5 (CH), 124.3 (CH), 127.3 (C), 133.4 (C), 135.4 (C),137.1 (C), 137.7 (C), 151.1 (C), and 153.3 (2×C). HRMS (ES) calcd. forC₂₁H₂₉N₂O₈S (MH⁺), 469.1639 found 469.1625. HPLC: tr=1.04 (98.3%)CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(2-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinolineF42

150 mg (71%), yellow powder, m.p. 68-70° C., ¹H NMR (270 MHz, CDCl₃) δ1.21 (3H, t, J=7.3 Hz), 2.77-2.91 (2H, m), 3.53-3.63 (3H, m), 3.71 (1H,d, J=15.1 Hz), 3.76 (2H, s), 3.78 (3H, s), 3.83 (3H, s), 4.41 (1H, t,J=4.7 Hz), 5.22 (2H, br), 6.60 (1H, s), 6.88 (1H, d, J=8.3 Hz), 6.94(1H, d, J=7.4 Hz), 7.21-7.28 (1H, m), 7.34 (1H, s), 7.43 (1H, dd, J=7.4and 1.2 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 15.6 (CH₃), 54.3 (CH₂), 55.4(CH₂), 55.6 (CH₂), 56.2 (CH₃), 56.3 (CH₃), 64.5 (CH₂), 73.44 (CH), 110.3(CH), 110.4 (CH), 120.4 (CH), 124.1 (CH), 125.4 (C), 128.1 (C), 128.3(CH), 130.4 (CH), 135.5 (C), 137.7 (C), 150.7 (C) and 157.8 (C). HRMS(ES) calcd. for C₂₀H₂₇N₂O₆S (MH⁺), 423.1584 found 423.1564. HPLC:tr=1.07 (95.5%) CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(3-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinolineF43

150 mg (72%), yellow powder, m.p. 47-48° C., ¹H NMR (270 MHz, CDCl₃) δ1.21 (3H, t, J=6.9 Hz), 2.80 (1H, d, J=4.8 Hz), 3.47-3.76 (6H, m), 3.79(6H, s), 4.42 (1H, t, J=4.8 Hz), 5.24 (2H, br), 6.60 (1H, s), 6.81 (1H,dd, J=8.0 and 2.5 Hz), 6.95-6.97 (2H, m), 7.24 (1H, t, J=8.0 Hz), 7.36(1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 15.6 (CH₃), 54.2 (CH₂), 55.2 (CH₃),55.7 (CH₂), 56.2 (CH₃), 62.3 (CH₂), 64.5 (CH₂), 73.3 (CH), 110.3 (CH),114.3 (CH), 121.3 (CH), 124.1 (CH), 128.2 (C), 129.3 (CH), 135.4 (C),137.6 (C), 139.2 (C), 150.7 (C), and 159.7 (C). HRMS (ES) calcd. forC₂₀H₂₇N₂O₄S (MH⁺), 423.1584 found 423.1576; HPLC: tr=1.74 (98.2%)CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(4-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroiso-quinolineF44

160 mg (77%), yellow powder, m.p. 128-130° C., ¹H NMR (270 MHz, CDCl₃) δ1.21 (3H, t, J=7.2 Hz), 2.80 (2H, d, J=4.8 Hz), 3.47-3.76 (6H, m), 3.79(6H, s), 3.80 (3H, s), 3.81 (3H, s), 4.41 (1H, t, J=4.8 Hz), 5.40 (2H,br), 6.60 (1H, s), 6.86 (2H, d, =8.0 Hz), 7.24 (2H, d, J=8.0 Hz), 7.36(1H, s); HRMS (ES) calcd. for C₂₀H₂₇N₂O₄S (MH⁺), 423.1584 found423.1579. HPLC: tr=1.34 (100%) CH₃CN/H₂O 90/10.

4-Ethoxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinolineF45

180 mg (75%), yellow powder, m.p. 77-79° C., ¹H NMR (270 MHz,CDCl₃/CD₃OD 5:1) δ 1.10 (3H, t, J=7.1 Hz), 2.68 (1H, d, J=4.7 Hz),3.34-3.65 (8H, m), 3.69 (3H, s), 3.70 (3H, s), 3.72 (3H, s), 4.32 (1H,t, J=4.7 Hz), 6.51 (2H, s), 6.53 (1H, s), 7.25 (1H, s); ¹³C NMR (100MHz, CDCl₃/CD₃OD 5:1) δ 15.1 (CH₃), 53.9 (CH₂), 55.5 (CH₂), 55.8(3×CH₃), 60.6 (CH₃), 62.3 (CH₂), 64.5 (CH₂), 73.3 (CH), 105.5 (2×CH),109.9 (CH), 123.5 (CH), 126.9 (C), 133.2 (C), 134.7 (C), 136.6 (C),137.6 (C), 151.1 (C) and 152.9 (2×C). HRMS (ES) calcd. for C₂₂H₃₁N₂O₈S(MH⁺), 483.1796 found 483.1793. HPLC: tr=1.59 (100%) CH₃CN/H₂O 90/10.

4-O-Acetyl-7-methoxy-2-(3-methoxy-benzyl)-6-sulfamoyloxy-1,2,3,4-tetrahydroisoquinolineF46

170 mg (79%), yellow powder, m.p. 65-66° C., ¹H NMR (270 MHz, CDCl₃) δ2.08 (3H, s), 2.73 (1H, dd, J=12.4 and 3.9 Hz), 2.95 (1H, dd, J=12.4 and3.9 Hz), 3.45 (1H, d, J=15.4 Hz), 3.60 (1H, d, J=13.2 Hz), 3.75-3.83(8H, m), 5.15 (2H, br), 5.86 (1H, t, J=3.9 Hz), 6.66 (1H, s), 6.81 (1H,dd, J=8.2 and 2.5 Hz), 6.93-6.95 (2H, m), 7.23 (1H, t, J=8.2 Hz), 7.29(1H, s); ¹³C NMR (100 MHz, CDCl₃) δ 21.3 (CH₃), 54.7 (CH₂), 55.2 (CH₃),55.3 (CH₂), 56.3 (CH₃), 61.9 (CH₂), 68.0 (CH), 110.6 (CH), 112.6 (CH),114.6 (CH), 121.2 (CH), 124.7 (CH), 125.3 (C), 129.3 (CH), 136.4 (C),137.7 (C), 139.0 (C), 151.3 (C), 159.7 (C), and 171.0 (CO). HRMS (ES)calcd. for C₂₀H₂₅N₂O₇S (MH⁺), 437.1377 found 437.1364. HPLC: tr=1.60(100%) CH₃CN/H₂O 90/10.

4,6-Diacetoxy-7-methoxy-2-(3-methoxy-benzyl)-1,2,3,4-tetrahydro-isoquinolin-4-ylester F47

A solution of7-Methoxy-2-(3-methoxy-benzyl)-1,2,3,4-tetrahydroisoquinoline-4,6-diol(158 mg, 0.5 mmol) in DCM (20 mL) and TEA (0.42 mL, 3 mmol) was cooledto 0° C. before Ac₂O (0.19 mL, 2 mmol) was added dropwise. The mixturewas stirred at 0° C. for 2 hours then rt for 1 hour. After addition ofwater (50 mL), the organics were extracted with DCM and the organiclayer washed with a solution of. NaHCO₃, water, brine, dried (MgSO₄),filtered and concentrated. The crude solid (0.22 g) was purified byflash chromatography to give 135 mg of a white powder (68%), m.p.112-114° C., ¹H NMR (270 MHz, CDCl₃) δ 2.07 (3H, s), 2.28 (3H, s), 2.71(1H, dd, J=12.4 and 3.6 Hz), 2.97 (1H, dd, J=12.4 and 3.6 Hz), 3.44 (1H,d, J=14.9 Hz), 3.60 (1H, d, J=13.2 Hz), 3.76-3.83 (8H, m), 5.88 (1H, t,J=3.6 Hz), 6.61 (1H, s), 6.80 (1H, dd, J=8.3 and 2.5 Hz), 6.94-6.96 (2H,m), 7.01 (1H, s), 7.23(1H, t, J=8.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 20.6(CH₃), 21.3 (CH₃), 54.7 (CH₂), 55.2 (CH₃), 55.5 (CH₂), 55.9 (CH₃), 61.9(CH₂), 68.5 (CH), 109.8 (CH), 112.7 (CH), 114.5 (CH), 121.2 (CH), 123.4(CH), 124.6 (C), 129.3 (CH), 135.0 (C), 138.5 (C), 139.2 (C), 151.0 (C),159.7 (C), 169.0 (CO), and 171.0 (CO). HRMS (ES) calcd. for C₂₂H₂₆NO₆(MH⁺), 400.1755 found 400.1756. HPLC: tr=1.91 (100%) CH₃CN/H₂O 90/10.

3-Ethyl-benzoic acid W1

Magnesium turnings (829 mg, 34.1 mmol) were placed in an oven-dried 50mL RBF and heated three times under high vacuum, then filled withnitrogen. The flask was sealed with a rubber septum and a pressurerelease system. Anhydrous THF (6.0 mL) and 1-bromo-3-ethylbenzene (297mg, 1.6 mmol) were added. The reaction mixture was heated to 50-60° C.for 5 min. 1-Bromo-3-ethylbenzene (5.812 g, 31.4 mmol) was dissolved inanhydrous THF (12.0 mL) and added drop-wise via syringe maintaining50-60° C. The reaction mixture was stirred for 2 h cooling to roomtemperature. The septum was replaced by a balloon with carbon dioxideand stirred for 16 h at room temperature. The reaction was quenched witha few grams of dry ice, acidified with hydrochloric acid (2M, 50 mL) andextracted with diethylether (2×100 mL). The combined organic layers werewashed with a solution of sodium hydroxide (1M, 100 mL). The organiclayer was disposed. The aqueous layer was acidified with hydrochloricacid (2M, 100 mL) and extracted with diethylether (2×100 mL). Thecombined organic of this extraction were dried (MgSO₄), filtered andconcentrated in vacuo. The title compound was obtained as pale pinkcrystalline solid (2.698 g, 54%).

¹H NMR (270 MHz, CDCl₃): δ 1.26 (3H, t, J 7.7, CH₂CH₃), 2.71 (2H, q, J7.6, CH₂CH₃), 7.37 (1H, t, J 7.3, CH), 7.43 (1H, t, J 7.7, CH),7.89-7.97 (1H, m, CH). ¹³C NMR (67.5 MHz, CDCl₃): δ 15.5, 28.6, 127.6,128.5, 129.3, 129.6, 133.5, 144.6, 172.7.

2-(3-Ethylbenzoyl)-3-methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW2

3-Methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahyoisoquinoline (425 mg, 1.5mmol) and W1 (339 mg, 2.25 mmol) were placed in an oven-dried tube anddissolved in anhydrous DCM (4.5 mL) and anhydrous THF (1.5 mL). EDCI(578 mg, 3.0 mmol) was added and the reaction mixture was stirred for 20h at room temperature. The reaction mixture was diluted withhydrochloric acid (1M, 50 mL) and extracted with DCM/ethyl acetate(˜9:1, 2×50 mL). The combined organic layers were filtered (MgSO₄) andconcentrated in vacuo. The residue was purified by flash columnchromatography using Flashmaster (SiO₂ (20 g, hexane to hexane/EtOAc70/30). W2 was obtained as colourless sticky foam (534 mg, 85%). ¹H NMR(270 MHz, CDCl₃) δ 1.14 (3H, s, br, CHCH₃), 1.24 (3H, t, J 7.6,ArCH₂CH₃), 2.28-2.56 (1H, m, br, one of ArCH₂CH), 2.67 (2H, q, J 7.5,ArCH₂CH₃), 3.06 (1H, d, br, J 11.6, one of ArCH₂CH), 3.85 (3H, s, OCH₃),4.17-4.54 (2H, m, br, CHCH₃, one of ArCH₂N), 5.06-5.44 (1H, m, br, oneof ArCH₂N), 5.11 (2H, s, OCH₂Ph), 6.44 (0.30×1H, s, br, CH), 6.63 (1H,s, br, CH), 6.68 (0.70×1H, s, br, CH), 7.16-7.47 (9H, m, OCH₂C₆H₅,4×CH).

2-(3-Ethylbenzyl)-7-methoxy-3-methyl-6-benzyloxy-1,2,3,4-tetrahydroisoquinolineW3

Lithium aluminium hydride (114 mg, 3.0 mmol) was placed in an oven-driedtube and covered with anhydrous THF (1.0 mL). W2 (250 mg, 0.6 mmol) wasdissolved in anhydrous THF (3.0 mL) and added drop-wise via syringe atroom temperature. The reaction mixture was stirred for 30 min at roomtemperature. EtOAc (5 mL) was added carefully. The mixture was thendiluted with EtOAc (100 mL) and standing for about 30 min in a beaker.After the salts settled the mixture was poured through a sinter funnelcontaining a pad of celite. The sinter was washed with EtOAc (4×10 mL)and the filtrate was concentrated in vacuo. W3 was obtained ascolourless oil (240 mg, 99%). ¹H NMR (270 MHz, CDCl₃) δ 1.13 (3H, d, J6.6, CHCH₃), 1.23 (3H, t, J 7.6, ArCH₂CH₃), 2.48 (1H, dd, J 16.1, 5.9,one of ArCH₂CH), 2.64 (2H, q, J 7.6, ArCH₂CH₃), 2.86 (1H, dd, J 16.0,4.7, one of ArCH₂CH), 3.06 (1H, sext, J 6.1, CHCH₃), 3.44-3.71 (3H, m,three of 2×ArCH₂N), 3.73-3.88 (1H, m, one of ArCH₂N), 3.79 (3H, s,OCH₃), 5.10 (2H, s, OCH₂Ph), 6.47 (1H, s, CH), 6.60 (1H, s, CH),7.06-7.51 (9H, m, OCH₂C₆H₅, 4×CH). ¹³C NMR (67.5 MHz, CDCl₃): δ 15.2,15.6, 28.8, 34.8, 51.4, 52.1, 56.0, 57.1, 71.1, 109.8, 114.4, 125.7,126.2, 126.4, 126.8, 127.2, 127.7, 128.4, 128.5, 137.3, 139.3, 144.2,146.6, 147.8.

2-(3-Ethyl-benzyl)-3-methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW4

Palladium on charcoal (10%, 30.9 mg) was covered with THF (8.0 mL) andethanol (8.0 mL). W3 (240 mg, 0.6 mmol) was added as solution in THF(16.0 mL). The mixture was heated twice to reflux using a heat gun andstirred under an atmosphere of hydrogen (balloon pressure) for 1 h atroom temperature. The reaction mixture was filtered through celite. Thecelite was washed with methanol (4×5 mL) and the combined filtrates wereconcentrated in vacuo. The residue was purified by flash columnchromatography using Flashmaster (SiO₂: 20 g, hexane 100% tohexane/ethyl acetate/methanol 49:50:1). W4 was obtained as pale yellowsolid (112 mg, 60%). ¹H NMR (270 MHz, CDCl₃) δ 1.16 (3H, d, J 6.6,CHCH₃), 1.24 (3H, t, J 7.6, ArCH₂CH₃), 2.51 (1H, dd, J 16.1, 6.2, one ofArCH₂CH), 2.64 (2H, q, J 7.5, ArCH₂CH₃), 2.90 (1H, dd, J 16.2, 5.0, oneof ArCH₂CH), 3.09 (1H, sext, J 6.1, CHCH₃), 3.49-3.67 (3H, m, three of2×ArCH₂N), 3.75-3.83 (1H, m, one of ArCH₂N), 3.79 (3H, s, OCH₃), 6.43(1H, s, CH), 6.63 (1H, s, br, CH), 7.07-7.14 (1H, m, CH), 7.15-7.29 (3H,m, 3×CH). ¹³C NMR (67.5 MHz, CDCl₃): δ 15.3, 15.6, 28.8, 34.5, 51.3,52.2, 55.9, 56.9, 108.6, 114.4, 125.3, 126.3, 126.4, 128.2, 128.5,139.1, 143.9, 144.3, 144.8. LC/MS (ES⁺) t_(r) 2.31 min; m/z 312.4((M+H)⁺, 100%); MeOH/H₂O 90:10 (1.0 mL/min), HPLC tr 3.45 min (99.3%);CH₃CN/H₂O 90:10 (1.0 mL/min).

2-(3-Ethyl-benzyl)-3-methyl-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinolineW5

W4 (93.5 mg, 0.3 mmol) was placed in an oven-dried 50 mL RBF anddissolved in anhydrous DMA (0.5 mL). Sulfamoyl chloride (0.45M intoluene, 2.0 mL, 0.9 mmol) was concentrated in vacuo and re-dissolved inanhydrous DMA (1.5 mL). This solution was added drop-wise via syringe at0° C. The reaction mixture was stirred for 18 h at room temperature. DCM(100 mL) was added and the mixture was washed with Na₂CO₃(half-saturated, 100 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by flash columnchromatography using Flashmaster (SiO₂: 20 g, hexane 100% tohexane/ethyl acetate 50/50. W5 was obtained as pale yellow solid (66 mg,56%) after re-crystallisation from diethyl ether. ¹H NMR (270 MHz,CDCl₃) δ 1.07 (3H, d, J 6.6, CHCH₃), 1.16 (3H, t, J 7.7, ArCH₂CH₃), 2.46(1H, dd, J 16.2, 5.8, one of ArCH₂CH), 2.57 (2H, q, J 7.6, ArCH₂CH₃),2.86 (1H, dd, J 16.2, 5.0, one of ArCH₂CH), 3.01 (1H, sext, J 5.9,CHCH₃), 3.41-3.62 (3H, m, three of 2×ArCH₂N), 3.66-3.77 (1H, m, one ofArCH₂N), 3.71 (3H, s, OCH₃), 6.21 (2H, s, br, NH₂), 6.49 (1H, s, CH),7.00 (1H, s, br, CH), 7.00-7.25 (4H, m, 4×CH).

¹³C NMR (67.5 MHz, CDCl₃): δ 14.9, 15.5, 27.5, 28.6, 51.1, 51.9, 55.9,57.0, 110.6, 124.0, 126.0, 126.3, 126.4, 128.1, 128.2, 133.5, 137.3,144.2, 149.5.

LC/MS (ES⁺) t_(r) 1.96 min; m/z 391.4 ((M+H)⁺, 100%); MeOH/H₂O 90:10(1.0 mL/min), HPLC tr 2.31 min (97.6%); CH₃CN/H₂O 90:10 (1.0 mL/min).

2-(2-Fluoro-5-methoxy-benzyl)-3-methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW6

3-Methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (339 mg,1.2 mmol) was dissolved in anhydrous DMF (3.6 mL), DIPEA (314 mg, 2.4mmol) and 2-fluoro-5-methoxybenzyl bromide (401 mg, 74 wt %, 1.35 mmol)were added. The mixture was heated to 80° C. for 20 h, cooled to roomtemperature and poured into water (50 mL) and ammonium chloride(saturated, 2 mL) The mixture was extracted with ethyl acetate (2×50mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography using Flashmaster (SiO₂: 20 g, hexane 100% tohexane/ethyl acetate 60/40). W6 compound was obtained as orange oil (363mg, 71%). ¹H NMR (270 MHz, CDCl₃) δ 1.14 (3H, d, J 6.3, CHCH₃), 2.47(1H, dd, J 16.2, 6.1, one of ArCH₂CH), 2.86 (1H, dd, J 16.2, 5.0, one ofArCH₂CH), 3.09 (1H, sext, J 6.1, CHCH₃), 3.54-3.68 (3H, m, three of2×ArCH₂N), 3.69-3.81 (1H, m, one of ArCH₂N), 3.75 (3H, s, OCH₃), 3.80(3H, s, OCH₃), 5.09 (2H, s, OCH₂Ph), 6.49 (1H, s, CH), 6.59 (1H, s, CH),6.72 (1H, dt, J 9.1, 3.7, CH), 6.94 (1H, t, J 9.1, CH), 7.01 (1H, dd, J5.9, 3.2, CH), 7.23-7.45 (5H, m, OCH₂C₆H₅). ¹³C NMR (67.5 MHz, CDCl₃): δ15.2, 34.8, 49.5 (d, J 1.5), 51.3, 52.4, 55.7, 56.0, 71.0, 109.8, 113.4(d, J 8.2), 114.4, 115.6 (dd, J 14.2, 9.5), 125.6, 126.5, 126.7, 127.0,127.2, 127.7, 128.4, 137.3, 146.6, 147.8, 154.0, 155.6 (d, J 2.1).

LC/MS (ES⁺) t_(r) 3.67 min; m/z 422.3 ((M+H)⁺, 100%); MeOH/H₂O 90:10(1.0 mL/min).

2-(2-Chloro-5-methoxy-benzyl)-3-methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW7

3-Methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (339 mg,1.2 mmol) was dissolved in anhydrous DMF (3.6 mL), DIPEA (315 mg, 2.4mmol) and 2-chloro-5-methoxybenzyl bromide (414 mg, 76 wt %, 1.34 mmol)were added. The mixture was heated to 80° C. for 20 h, cooled to roomtemperature and poured into water (50 mL) and ammonium chloride(saturated, 2 mL). The mixture was extracted with ethyl acetate (2×50mL). The combined organic layers were dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography using Flashmaster (SiO₂: 20 g, hexane 100% tohexane/ethyl acetate 70/30). W7 was obtained as orange oil (407 mg,77%). ¹H NMR (270 MHz, CDCl₃) δ 1.13 (3H, d, J 6.6, CHCH₃), 2.48 (1H,dd, J 16.0, 5.8, one of ArCH₂CH), 2.90 (1H, dd, J 16.0, 5.0, one ofArCH₂CH), 3.13 (1H, sext, J 6.0, CHCH₃), 3.58-3.84 (4H, m, 2×ArCH₂N),3.77 (3H, s, OCH₃), 3.81 (3H, s, OCH₃), 5.11 (2H, s, OCH₂Ph), 6.50 (1H,s, CH), 6.61 (1H, s, CH), 6.72 (1H, dd, J 8.7, 3.2, CH), 7.14 (1H, d, J3.0, CH), 7.23 (1H, d, J 8.8, CH), 7.24-7.47 (5H, m, OCH₂C₆H₅). ¹³C NMR(67.5 MHz, CDCl₃): δ 15.2, 34.7, 51.2, 52.5, 53.8, 55.5, 56.0, 71.1,109.8, 113.5, 114.4, 115.7, 125.3, 125.6, 126.7, 127.3, 127.7, 128.5,129.9, 137.3, 138.1, 146.7, 147.8, 158.3. LC/MS (ES⁺) t_(r) 5.29 min;m/z 438.4 ((M+H)⁺, 100%); MeOH/H₂O 90:10 (1.0 mL/min).

2-(2,5-Dimethoxy-benzyl)-3-methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW8

3-Methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (338 mg,1.2 mmol) was dissolved in anhydrous DMF (3.6 mL), DIPEA (314 mg, 2.4mmol) and 2,5-dimethoxybenzyl chloride (279 mg, 1.5 mmol) were added.The mixture was heated to 80° C. for 20 h, cooled to room temperatureand poured into water (50 mL) and ammonium chloride (saturated, 2 mL).The mixture was extracted with ethyl acetate (2×50 mL). The combinedorganic layers were dried (MgSO₄), filtered and concentrated in vacuo.The residue was purified by flash column chromatography usingFlashmaster (SiO₂: 20 g, hexane 100% to hexane/ethyl acetate 50/50). W8was obtained as sticky orange oil (395 mg, 76%). ¹H NMR (270 MHz, CDCl₃)δ 1.14 (3H, d, J 6.3, CHCH₃), 2.48 (1H, dd, J 16.3, 6.0, one ofArCH₂CH), 2.86 (1H, dd, J 16.1, 4.8, one of ArCH₂CH), 3.11 (1H, sext, J6.1, CHCH₃), 3.58-3.77 (4H, m, 2×ArCH₂N), 3.76 (3H, s, OCH₃), 3.77 (3H,s, OCH₃), 3.81 (3H, s, OCH₃), 5.11 (2H, s, OCH₂Ph), 6.50 (1H, s, CH),6.61 (1H, s, CH), 6.74 (1H, dd, J 8.8, 3.0, CH), 6.80 (1H, d, J 8.8,CH), 7.07 (1H, d, J 2.8, CH), 7.24-7.47 (5H, m, OCH₂C₆H₅). ¹³C NMR (67.5MHz, CDCl₃): δ 15.5, 34.5, 50.0, 51.4, 52.4, 55.7, 56.0, 56.0, 71.0,109.9, 111.3, 111.9, 114.4, 116.0, 125.8, 127.0, 127.2, 127.7, 128.4,128.9, 137.3, 146.5, 147.7, 151.9, 153.6.

2-(2-Fluoro-5-methoxy-benzyl)-3-methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW9

Palladium on charcoal (10%, 30.4 mg) was covered with THF (8.0 mL) andethanol (8.0 mL). W6 (337 mg, 0.8 mmol) was added as solution in THF(16.0 mL). The mixture was heated twice to reflux using a heat gun andstirred under an atmosphere of hydrogen (balloon pressure) for 2 h atroom temperature. The reaction mixture was filtered through celite. Thecelite was washed with ethyl acetate (5×20 mL) and methanol (5×20 mL)and the combined filtrates were concentrated in vacuo. The residue waspurified by flash column chromatography (SiO₂: 20 g, chloroform/acetone95:5 to 90:10). W9 was obtained as pale yellow solid (221 mg, 83%). Asmall sample (22 mg) was further purified by preparative HPLC (RP18,acetonitrile/water 90:10). ¹H NMR (270 MHz, CDCl₃) δ 1.13 (3H, d, J 6.3,CHCH₃), 2.49 (1H, dd, J 16.1, 5.9, one of ArCH₂CH), 2.88 (1H, dd, J16.1, 4.8, one of ArCH₂CH), 3.09 (1H, sext, J 6.1, CHCH₃), 3.52-3.66(3H, m, three of 2×ArCH₂N), 3.67-3.81 (1H, m, one of ArCH₂N), 3.75 (3H,s, OCH₃), 3.79 (3H, s, OCH₃), 6.44 (1H, s, CH), 6.62 (1H, s, CH), 6.72(1H, dt, J 8.8, 3.6, CH), 6.93 (1H, t, J 9.1, CH), 7.01 (1H, dd, J 5.6,3.3, CH). LC/MS (ES⁺) t_(r) 2.00 min; m/z 332.4 ((M+H)⁺, 100%); MeOH/H₂O90:10 (1.0 mL/min).

2-(2-Chloro-5-methoxy-benzyl)-3-methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW10

Palladium on charcoal (10%, 30.6 mg) was covered with THF (8.0 mL) andethanol (8.0 mL). W7 (350 mg, 0.8 mmol) was added as solution in THF(16.0 mL). The mixture was heated twice to reflux using a heat gun andstirred under an atmosphere of hydrogen (balloon pressure) for 2 h atroom temperature. The reaction mixture was filtered through celite. Thecelite was washed with ethyl acetate (5×20 mL) and methanol (5×20 mL)and the combined filtrates were concentrated in vacuo. The residue waspurified by flash column chromatography using Flashmaster (SiO₂: 20 g,hexane 100% to hexane/ethyl acetate/methanol 69:30:1). W10 was obtainedas pale yellow solid (150 mg, 54%). ¹H NMR (270 MHz, CDCl₃) δ 1.14 (3H,d, J 6.3, CHCH₃), 2.50 (1H, dd, J 16.0, 5.8, one of ArCH₂CH), 2.92 (1H,dd, J 16.2, 5.0, one of ArCH₂CH), 3.14 (1H, sext, J 6.1, CHCH₃),3.57-3.84 (4H, m, 2×ArCH₂N), 3.77 (3H, s, OCH₃), 3.80 (3H, s, OCH₃),5.11 (1H, s, br, OH), 6.45 (1H, s, CH), 6.64 (1H, s, CH), 6.73 (1H, dd,J 8.8, 3.0, CH), 7.16 (1H, d, J 3.1, CH), 7.23 (1H, d, J 8.5, CH).

¹³C NMR (67.5 MHz, CDCl₃): δ 15.2, 34.5, 51.3, 52.6, 53.7, 55.5, 55.9,108.6, 113.5, 114.5, 115.6, 125.3, 125.4, 126.4, 129.8, 138.1, 143.9,144.8, 158.3. LC/MS (ES⁺) t_(r) 2.41 min; m/z 348.4 ((M+H)⁺, 100%);MeOH/H₂O 90:10 (1.0 mL/min), HPLC tr 2.76 min (99.2%); CH₃CN/H₂O 90:10(1.0 mL/min).

2-(2,5-Dimethoxy-benzyl)-3-methyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW11

Palladium on charcoal (10%, 30.9 mg) was covered with THF (8.0 mL) andethanol (8.0 mL). W8 (346 mg, 0.8 mmol) was added as solution in THF(16.0 mL). The mixture was heated twice to reflux using a heat gun andstirred under an atmosphere of hydrogen (balloon pressure) for 2 h atroom temperature. The reaction mixture was filtered through celite. Thecelite was washed with ethyl acetate (5×20 mL) and methanol (5×20 mL)and the combined filtrates were concentrated in vacuo. The residue waspurified by flash column chromatography using Flashmaster (SiO₂: 20 g,ethyl acetate/methanol 99:1). W11 was obtained as pale yellow solid (230mg, 83%). A small sample (24 mg) was further purified by preparativeHPLC (RP18, acetonitrile/water 90:10). ¹H NMR (270 MHz, CDCl₃) δ 1.14(3H, d, J 6.3, CHCH₃), 2.49 (1H, dd, J 16.1, 6.2, one of ArCH₂CH), 2.87(1H, dd, J 16.1, 4.8, one of ArCH₂CH), 3.11 (1H, sext, J 6.2, CHCH₃),3.56-3.71 (4H, m, 2×ArCH₂N), 3.74 (3H, s, OCH₃), 3.76 (3H, s, OCH₃),3.78 (3H, s, OCH₃), 5.56 (1H, s, br, OH), 6.44 (1H, s, CH), 6.61 (1H, s,CH), 6.73 (1H, dd, J 8.8, 2.7, CH), 6.79 (1H, d, J 8.8, CH), 7.07 (1H,d, J 2.8, CH). ¹³C NMR (67.5 MHz, CDCl₃): δ 15.5, 34.3, 50.0, 51.5,52.5, 55.7, 55.9, 56.0, 108.7, 111.4, 112.0, 114.5, 116.0, 125.6, 126.6,128.9, 143.8, 144.8, 152.0, 153.6. LC/MS (ES⁺) t_(r) 1.72 min; m/z 344.5((M+H)⁺, 100%); MeOH/H₂O 90:10 (1.0 mL/min).

2-(2-Fluoro-5-methoxy-benzyl)-3-methyl-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinolineW12

W9 (199 mg, 0.6 mmol) was placed in an oven-dried 50 mL RBF anddissolved in anhydrous DMA (2.0 mL). Sulfamoyl chloride (0.45M intoluene, 6.7 mL, 3.0 mmol) was concentrated in vacuo and re-dissolved inanhydrous DMA (3.0 mL). This solution was added drop-wise via syringe at0° C. The reaction mixture was stirred for 2 h at room temperature. DCM(100 mL) was added and the mixture was washed with Na₂CO₃(half-saturated, 100 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by flash columnchromatography using Flashmaster (SiO₂: 20 g, hexane 100% tohexane/ethyl acetate 50/50). W12 compound was obtained as white solid(43 mg, 17%) after re-crystallisation from diethyl ether. ¹H NMR (270MHz, CDCl₃) δ 1.16 (3H, d, J 6.3, CHCH₃), 2.54 (1H, dd, J 16.1, 5.4, oneof ArCH₂CH), 2.94 (1H, dd, J 16.2, 4.4, one of ArCH₂CH), 3.12 (1H, sext,J 5.9, CHCH₃), 3.56-3.83 (4H, m, 2×ArCH₂N), 3.77 (3H, s, OCH₃), 3.80(3H, s, OCH₃), 6.49 (2H, s, br, NH₂), 6.60 (1H, s, CH), 6.74 (1H, dt, J8.8, 3.7, CH), 6.95 (1H, t, J 9.4, CH), 6.96-7.04 (1H, m, CH), 7.08 (1H,s, CH). LC/MS (ES⁺) t_(r) 1.72 min; m/z 411.4 ((M+H)⁺, 100%); MeOH/H₂O90:10 (1.0 mL/min), HPLC tr 1.79 min (97.1%); CH₃CN/H₂O 90:10 (1.0mL/min).

2-(2-Chloro-5-methoxy-benzyl)-3-methyl-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinolineW13

W10 (105 mg, 0.3 mmol) was placed in an oven-dried 50 mL RBF anddissolved in anhydrous DMA (0.5 mL). Sulfamoyl chloride (0.45M intoluene, 3.3 mL, 1.5 mmol) was concentrated in vacuo and re-dissolved inanhydrous DMA (1.5 mL). This solution was added drop-wise via syringe at0° C. The reaction mixture was stirred for 18 h at room temperature. DCM(100 mL) was added and the mixture was washed with Na₂CO₃(half-saturated, 100 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by flash columnchromatography using (SiO₂: 20 g, chloroform/acetone 95:5 to 90:10). W13was obtained as yellow glass (61 mg, 47%). ¹H NMR (270 MHz, CDCl₃) δ1.15 (3H, d, J 6.6, CHCH₃), 2.55 (1H, dd, J 16.3, 5.5, one of ArCH₂CH),2.97 (1H, dd, J 16.1, 4.8, one of ArCH₂CH), 3.16 (1H, sext, J 6.0,CHCH₃), 3.60-3.74 (3H, m, three of 2×ArCH₂N), 3.75-3.85 (1H, m, one of2×ArCH₂N), 3.79 (3H, s, OCH₃), 3.81 (3H, s, OCH₃), 6.15 (1H, s, br,NH₂), 6.60 (1H, s, CH), 6.74 (1H, dd, J 8.7, 3.2, CH), 7.09 (1H, s, CH),7.12 (1H, d, J 3.4, CH), 7.25 (1H, d, J 8.8, CH). ¹³C NMR (67.5 MHz,CDCl₃): δ 15.0, 34.3, 51.1, 52.3, 53.9, 55.4, 56.0, 87.5, 110.7, 113.4,115.8, 124.2, 126.5, 129.9, 133.7, 137.4, 137.7, 149.5, 158.3.

2-(2,5-Dimethoxy-benzyl)-3-methyl-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinolineW14

W11 (206 mg, 0.6 mmol) was placed in an oven-dried 50 mL RBF anddissolved in anhydrous DMA (1.0 mL). Sulfamoyl chloride (0.45M intoluene, 6.7 mL, 2.5 mmol) was concentrated in vacuo and re-dissolved inanhydrous DMA (2.0 mL). This solution was added drop-wise via syringe at0° C. The reaction mixture was stirred for 18 h at room temperature. DCM(100 mL) was added and the mixture was washed with Na₂CO₃(half-saturated, 100 mL). The organic layer was dried (MgSO₄), filteredand concentrated in vacuo. The residue was purified by flash columnchromatography using Flashmaster (SiO₂: 20 g, hexane 100% tohexane/ethyl acetate 30/70 and flash column chromatography (SiO₂: 20 g,chloroform/acetone 80:20 to 75:25). The product was re-crystallised fromdiisopropylether and washed with diethylether (˜20×1 mL). W14 wasobtained as white solid (33 mg, 12%) containing still diisopropylether(5.1 wt % by ¹H NMR). ¹H NMR (270 MHz, CDCl₃) δ 1.12 (3H, d, J 6.3,CHCH₃), 2.51 (1H, dd, J 16.0, 6.1, one of ArCH₂CH), 2.90 (1H, dd, J16.2, 4.7, one of ArCH₂CH), 3.11 (1H, sext, J 6.0, CHCH₃), 3.54-3.71(4H, m, 2×ArCH₂N), 3.73 (3H, s, OCH₃), 3.75 (3H, s, OCH₃), 3.77 (3H, s,OCH₃), 5.82 (2H, s, br, NH₂), 6.56 (1H, s, CH), 6.71 (1H, dd, J 8.8,3.0, CH), 6.77 (1H, d, J 8.8, CH), 7.01 (1H, d, J 2.8, CH), 7.04 (1H, s,CH). ¹³C NMR (67.5 MHz, CDCl₃): δ 15.0, 33.9, 49.8, 51.1, 52.0, 55.3,55.7, 110.4, 111.2, 111.5, 115.7, 123.8, 126.2, 128.4, 133.6, 137.1,149.4, 151.6, 153.3. LC/MS (ES⁺) t_(r) 1.96 min; m/z 423.3 ((M+H)⁺,100%); MeOH/H₂O 90:10 (1.0 mL/min), HPLC tr 2.46 min (99.3%); CH₃CN/H₂O90:10 (1.0 mL/min).

4-Ethoxy-3,5-dimethoxy-benzoic acid ethyl ester W15

Syringic acid (3.962 g, 20.0 mmol) and potassium carbonate (11.058 g,80.0 mmol) were placed in a 500 mL RBF and covered with anhydrous DMF(30 mL). Iodoethane (6.898 g, 44.2 mmol) was added drop-wise and thereaction mixture stirred at room temperature for 18 h. The reactionmixture was diluted with water (400 mL) and extracted with DCM/ethylacetate (˜9:1; 2×200 mL). The combined organics were dried (MgSO₄),filtered and concentrated in vacuo to give W15 as brown oil whichsolidified upon standing overnight (3.185 g; 62%). ¹H NMR (270 MHz,CDCl₃): δ 1.34 (3H, t, J 7.2, OCH₂CH₃), 1.37 (3H, t, J 7.0, OCH₂CH₃),3.87 (6H, s, 2'OCH₃), 4.09 (2H, q, J 7.1, OCH₂CH₃), 4.35 (2H, q, J 7.1,OCH₂CH₃), 7.27 (2H, s, 2×CH). ¹³C NMR (67.5 MHz, CDCl₃): δ 14.4, 15.5,56.2, 61.1, 69.0, 106.6, 125.3, 140.9, 153.2, 166.3.

4-Ethoxy-3,5-dimethoxy-benzoic acid W16

W15 (3.177 g, 12.5 mmol) was dissolved in methanol (37.5 mL) and sodiumhydroxide (2.021 g, 50.5 mmol) was added as solution in water (12.5 mL).The reaction mixture was heated for 2 h at 60° C. The reaction mixturewas concentrated in vacuo, diluted with hydrochloric acid (2M, 100 mL)and extracted with ethyl acetate (2×100 mL). The combined organics weredried (MgSO₄), filtered and concentrated in vacuo to give W16 as beigesolid (2.744 g; 97%). ¹H NMR (270 MHz, CDCl₃): δ 1.31 (3H, dt, J 7.0,1.4, OCH₂CH₃), 3.84 (6H, d, J 1.4, 2×OCH₃), 4.07 (2H, dq, J 7.0,OCH₂CH₃), 7.29 (2H, d, J 1.6, 2×CH), 10.04 (1H, s, br, CO₂H). ¹³C NMR(67.5 MHz, CDCl₃): δ 15.4, 56.1, 68.9, 106.8, 125.2, 140.9, 153.1,169.1.

2-(4-Ethoxy-3,5-dimethoxybenzoyl)-3-ethyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW17

3-Methyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline (356 mg,1.2 mmol) and W16 (406 mg, 1.8 mmol) were placed in an oven-dried tubeand dissolved in anhydrous DCM (4.5 mL) and anhydrous THF (1.5 mL). EDCI(460 mg, 2.4 mmol) was added and the reaction mixture was stirred for 22h at room temperature. The reaction mixture was diluted with DCM (50mL), washed with hydrochloric acid (1M, 20 mL) and brine (20 mL). Thecombined organics were filtered (MgSO₄) and concentrated in vacuo. Theresidue was purified by flash column chromatography using Flashmaster(SiO₂ (20 g), hexane to hexane/ethyl acetate 60/40). W17 was obtained ascolourless glass (534 mg, 88%). ¹H NMR (270 MHz, CDCl₃): δ 0.80(0.67×3H, t, J 10.7, CHCH₂CH₃), 1.01 (0.33×3H, s, br, CHCH₂CH₃), 1.34(3H, t, J 7.0, OCH₂CH₃), 1.44-1.78 (2H, m, CHCH₂CH₃), 2.36-2.62 (1H, m,one of ArCH₂CH), 3.04 (1H, dd, 15.4, 4.4, one of ArCH₂CH), 3.77(0.40×3H, s, br, OCH₃), 3.82 (6H, s, 2×OCH₃), 3.85 (0.60×3H, s, br,OCH₃), 3.97-4.11 (1H, m, CHCH₂CH₃), 4.05 (2H, q, J 10.5, OCH₂CH₃), 4.15(0.35×1H, s, br, one of ArCH₂N), 4.39 (0.60×1H, dd, J 57.8, 15.1, one ofArCH₂N), 4.97 (0.40×1H, s, br, one of ArCH₂N), 5.09 (2H, s, OCH₂Ph),5.29 (0.65×1H, d, J 17.3, one of ArCH₂N), 6.41 (0.30×1H, s, br, CH),6.60 (3H, s, 3×CH), 6.66 (0.70×1H, s, CH), 7.23-7.45 (5H, m, OCH₂C₆H₅).

2-(4-Ethoxy-3,5-dimethoxy-benzyl)-3-ethyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline W18

Lithium aluminium hydride (113 mg, 3.0 mmol) was placed in an oven-driedtube and covered with anhydrous THF (2.0 mL). W17 (505 mg, 1.0 mmol) wasdissolved in anhydrous THF (6.0 mL) and added dropwise via syringe atroom temperature. The reaction mixture was stirred for 4 h at roomtemperature. Ethyl acetate (5 mL) was added carefully. The mixture wasthen diluted with ethyl acetate (100 mL) and standing for about 30 minin a beaker. After the salts settled the mixture was poured through asinter funnel containing a pad of celite. The sinter was washed withethyl acetate (4×10 mL) and the filtrate was concentrated in vacuo. W18was obtained as colourless sticky oil (463 mg, 94%). ¹H NMR (270 MHz,CDCl₃): δ 0.97 (3H, t, J 7.3, CH₂CH₃), 1.34 (3H, t, J 7.0, CH₂CH₃),1.38-1.54 (1H, m, one of CHCH₂CH₃), 1.66 (1H, sext, J 6.7, one ofCHCH₂CH₃), 2.48 (1H, dd, J 16.2, 6.1, one of ArCH₂CH), 2.78 (1H, dd, J16.4, 4.8, one of ArCH₂CH), 2.82-2.94 (1H, m, ArCH₂CH), 3.52-3.74 (4H,m, 2×ArCH₂N), 3.80 (3H, s, OCH₃), 3.81 (6H, s, 2×OCH₃), 4.03 (2H, q, J7.0, OCH₂CH₃), 5.10 (2H, s, OCH₂Ph), 6.49 (1H, s, CH), 6.58 (2H, s,2×CH), 6.62 (1H, s, CH), 7.22-7.46 (5H, m, OCH₂C₆H₅).

2-(4-Ethoxy-3,5-dimethoxy-benzyl)-3-ethyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinolineW19

Palladium on charcoal (29.3 mg) was placed in a 50 mL RBF and coveredwith THF (2.0 mL) and ethanol (2.0 mL). The flask was closed with aballoon containing hydrogen. The mixture was stirred for 30 min. ThenW18 (443 mg, 0.9 mmol) was dissolved in THF (6.0 mL) and added drop-wisevia syringe. The reaction mixture was stirred for 6 h at roomtemperature, filtered through a sinter funnel containing a pad ofcelite. The sinter was washed with ethyl acetate (4×5 mL) and methanol(4×5 mL). The residue was purified by flash column chromatography usingFlashmaster (SiO₂: 20 g, hexane to hexane/ethyl acetate/methanol49/50/1). W19 was obtained as pale yellow solid (236 mg, 65%). ¹H NMR(270 MHz, CDCl₃): δ 0.97 (3H, t, J 7.3, CH₂CH₃), 1.34 (3H, t, J 7.0,CH₂CH₃), 1.35-1.50 (1H, m, one of CHCH₂CH₃), 1.57-1.76 (1H, m, one ofCHCH₂CH₃), 2.50 (1H, dd, J 16.1, 5.9, one of ArCH₂CH), 2.79 (1H, dd, J16.4, 5.1, one of ArCH₂CH), 2.83-2.94 (1H, m, ArCH₂CH), 3.51-3.72 (4H,m, 2×ArCH₂N), 3.79 (3H, s, OCH₃), 3.80 (6H, s, 2×OCH₃), 4.02 (2H, q, J7.1, OCH₂CH₃), 6.44 (1H, s, CH), 6.58 (2H, s, 2×CH), 6.64 (1H, s, CH).

2-(4-Ethoxy-3,5-dimethoxy-benzyl)-3-ethyl-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinolineW20

W19 (200 mg, 0.5 mmol) was placed in an oven-dried 50 mL RBF anddissolved in anhydrous DMA (0.5 mL). Sulfamoyl chloride (0.65M intoluene, 3.8 mL, 2.5 mmol) was concentrated in vacuo and re-dissolved inanhydrous DMA (1.5 mL). This solution was added dropwise via syringe at0° C. The reaction mixture was stirred for 18 h at room temperature. DCM(50 mL) was added and the mixture was washed with Na₂CO₃(half-saturated, 50 mL). The residue was purified by flash columnchromatography using Flashmaster (SiO₂: 20 g, hexane to hexane/ethylacetate 70/30). W20 was obtained as pale yellow fluffy solid (177 mg,73%) after re-dissolving in diethyl ether/DCM (˜9:1, ˜10 mL) andremoving the solvent in vacuo very quickly. ¹H NMR (400 MHz, CDCl₃): δ0.98 (3H, t, J 7.4, CH₂CH₃), 1.34 (3H, t, J 7.0, CH₂CH₃), 1.40 (1H,sext, J 6.8, one of CHCH₂CH₃), 1.66 (1H, sext, J 6.7, one of CHCH₂CH₃),2.54 (1H, dd, J 16.0, 5.5, one of ArCH₂CH), 2.83 (1H, dd, J 15.3, 5.1,one of ArCH₂CH), 2.83-2.92 (1H, m, ArCH₂CH), 3.54-3.74 (4H, m,2×ArCH₂N), 3.78 (3H, s, OCH₃), 3.81 (6H, s, 2×OCH₃), 4.02 (2H, q, J 7.0,OCH₂CH₃), 6.57 (1H, s, CH), 6.58 (2H, s, 2×CH), 7.05 (1H, s, CH). ¹³CNMR (100 MHz, CDCl₃): δ 11.0, 15.5, 22.9, 29.1, 50.9, 55.4, 56.0, 56.1,58.0, 68.8, 105.2, 111.0, 124.4, 127.2, 134.3, 135.0, 135.5, 137.2,149.3, 153.3. LC/MS (ES⁺) t_(r) 1.83 min; m/z 481.7 ((M+H)⁺, 100%);MeOH/H₂O 90:10 (1.0 mL/min), HPLC tr 2.02 min (98.2%); CH₃CN/H₂O 90:10(1.0 mL/min).

B1 1,2,3,4-tetrahydroisoquinolin-6-ol hydrobromide

6-Methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (300 mg, 1.5mmol), was dissolved in 48% HBr in water (6 mL) and heated at 120° C.for 18 hours. The mixture was cooled and concentrated in vacuo prior tore-evaporation from ethanol (5 mL). Crystallisation from hot ethanolafforded B1 as a tan solid (256 mg, 74%). ¹H NMR (270 MHz, CDCl₃) δ 2.91(2H, t, J=6.3), 3.33 (2H, t, J=6.3), 4.14 (2H, s), 6.60 (1H, s), 6.69(1H, d, J=), 7.01 (1H, d, J=8.3), 8.97 (2H, br s), 9.47 (1H, br s);LC/MS (ES+) t_(r)=1.34 min , m/z 150.2 (M⁺+H); HPLC t_(r)=2.586 min(>99%)

B2 2-Piperonyl-1,2,3,4-tetrahydroisoquinolin-6-ol

An ice cold solution of amine B1 (345 mg, 1.5 mmol) and piperonylic acid(374 mg, 2.25 mmol) in DCM (10 mL) was treated with EDCI (575 mg, 3mmol) then triethylamine (251 μL, 1.8 mmol) and the solution stirred for30 minutes prior to warming to room temperature and stirring for 18hours. The resultant solution was diluted with DCM and washed with water(10 mL), 1M HCl (10 mL), NaHCO₃ (sat.) and brine, dried over MgSO₄filtered and solvent evaporated under reduced pressure. Purification bycolumn chromatography afforded both the amide B2 in 37% (164 mg) and theproduct with the additional phenolic ester B3 52 mg.

B2 2-Piperonyl-1,2,3,4-tetrahydroisoquinolin-6-ol

Gummy foam; m.p. 63-87° C.; ¹H NMR (270 MHz, CDCl₃) δ 2.92 (2H, br s),3.78 (2H, br s), 4.77 (2H, br s), 6.00 (2H, s), 6.07 (2H, s), 6.81-7.05(7H, m), 7.58 (1H, d, J=1.4), 7.80 (1H, dd, J=1.6, 8.3); HRMS (ESI+)calcd. for C₁₇H₁₆NO₃ (M⁺+H) 298.1060, found 298.1065; LC/MS (APCI)t_(r)=1.54 min, m/z 298.4 (M⁺+H); HPLC t_(r)=1.452 min (>97%).

B3 2-Piperonyl-1,2,3,4-tetrahydroisoquinolin-6-O-piperonyl ester

Mixture of rotamers; m.p. 63-78° C.; ¹H NMR (270 MHz, CDCl₃) δ 2.92 (2H,br s), 3.78 (2H, br s), 4.77 (2H, br s), 6.00 (2H, s), 6.07 (2H, s),6.82-7.01 (7H, m), 7.58 (1H, d, J=1.4), 7.79 (1H, dd, J=1.6, 8.3); HRMS(ESI+) calcd. for C₂₅H₂₀NO₇ (M⁺+H) 446.1234, found 446.1235; LC/MS(APCI) t_(r)=2.48 min, m/z 446.1 (M⁺+H); HPLC t_(r)=1.803 min (>95%).

B4 2-(3-Ethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 3-ethoxybenzoic acid (274 mg, 1.65 mmol) werereacted as described for the synthesis of B2. 83% (372 mg). m.p.150-151° C.; R_(f): 0.25 (petrol 40-60° C.:ethylacetate; 1:1); ¹H NMR(270 MHz, CDCl₃) δ 1.38 (3H, t, J=6.9), 2.72 and 2.82 (2H, m), 3.58 and3.92 (2H, m), 3.94-4.03 (2H, m), 4.48 and 4.78 (2H, br s), 6.58 (1H, s),6.62 and 6.98 (1H, m), 6.67-6.71 (1H, m), 6.90-6.96 (3H, m), 7.25-7.33(1H, m), 7.76 (1H, br s); HRMS (ESI+) calcd. for C₁₈H₂₀NO₃ (M⁺+H)298.1438, found 298.1440; LC/MS (APCI) t_(r)=1.58 min (>?%), m/z 298.4(M⁺+H); HPLC t_(r)=1.561 min (>99%).

B5 2-(3,4,5-Trimethoxyphenylacetyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 3,4,5-trimethoxyphenylacetic acid (373 mg,1.65 mmol) were reacted as described for the synthesis of B2. 88% (470mg). Gummy foam m.p. 37-53° C.; ¹H NMR (270 MHz, CDCl₃) δ 2.66 and 2.78(2H, t, J=6.2), 3.64 and 3.81 (2H, t, J=6.2), 3.70-3.82 (9H, m), 4.55and 4.67 (2H, s), 5.50 (1H, br s), 6.39 and 6.46 (2H, s), 6.56-6.68 (2H,m), 6.83 and 6.97 (1H, d, J=8.1), 7.25 (1H, s); HRMS (ESI+) calcd. forC₂₀H₂₄NO₅ (M⁺+H) 358.1649, found 358.1643; Anal. calcd. for CHNO: C, H,N. found: C, H, N%; LC/MS (APCI) t_(r)=1.30 min, m/z 358.3 (M⁺+H); HPLCt_(r)=1.447 min (>99%)

B6 2-(3,4-Diethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 3,4-diethoxybenzoic acid (347 mg, 1.65 mmol)were reacted as described for the synthesis of B2. Purification bycolumn chromatography afforded B6 (39 mg, 8%) together with 242 mg ofmaterial contaminated with 8% of the ester/amide. B6 shows m.p. 149-160°C.; ¹H NMR (270 MHz, CDCl₃) δ 1.38-1.49 (6H, m), 2.81 (2H, br s), 3.68and 3.89 (2H, br s), 4.02-4.16 (4H, m), 4.61 and 4.73 (2H, br s), 6.60(1H, d, J=4.1), 6.68 (1H, br s), 6.68 (1H, br s), 6.84-6.89 (1H, m),6.96-7.05 (2H, m), 7.16 (1H, br s); HRMS (ESI+) calcd. for C₂₀H₂₄NO₄(M⁺+H) 342.1700, found 342.1693; LC/MS (APCI) t_(r)=1.57 min, m/z 342.3(M⁺+H). HPLC t_(r)=1.525 min (>97%).

B7 2-(2,5-Dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 2,5-dimethoxybenzoic acid (301 mg, 1.65 mmol)were reacted as described for the synthesis of B2. Foam. m.p. 61-86° C.;¹H NMR (270 MHz, CDCl₃) δ 2.63-2.71 (1H, m), 2.79 (1H, t, J=6.1), 3.43and 3.69 (2H, m), 3.64-3.73 (6H, m), 3.80 and 4.01 (1H, m), 4.34 (1H,app q, J=15.7), 4.80 (1H, s)<6.54-6.68 (2H, m), 6.79-6.92 (4H, m), 7.72and 7.81 (1H, br s); HRMS (ES+) calcd. for C₁₈H₂₀NO₄ (M⁺+H) 314.1387,found 314.1376; LC/MS (APCI) t_(r)=1.86 min, m/z 314.3 (M⁺+H); HPLCt_(r)=2.097 min (>99%)

B8 2-(2,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amine hydrobromide salt (345 mg, 1.5 mmol) and 2,4-dimethoxybenzoicacid were reacted as described for the synthesis of B2. Purification bycolumn chromatography afforded B8 (265 mg, 56%). m.p. 62-87° C.; R_(f):0.25 (1:2, petrol:ethyl acetate); ¹H NMR (270 MHz, CDCl₃) δ 2.72 and2.86 (2H, m), 3.46 (1H, m), 3.68 and 3.78 (3H, s), 3.82 (3H, s), 4.09and 4.32 (1H, m), 4.81 (1H, s), 5.27 and 5.35 (1H, s), 6.45-6.76 (4H,m), 7.16-7.21 (2H, m); HRMS (ES+) calcd. for C₁₈H₂₀NO₄ (M⁺+H) 314.1387,found 314.1384; LC/MS (APCI) t_(r)=1.75 min, m/z 314.1 (M⁺+H); HPLCt_(r)=1.450 min (>97%)

B9 2-(2,3-Dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 2,3-dimethoxybenzoic acid (301 mg, 1.65 mmol)were reacted as described for the synthesis of B2. Purification bycolumn chromatography afforded the B9 (262 mg, 56%). m.p. 167-172° C.;R_(f): 0.32 (1:2, petrol:ethyl acetate); ¹H NMR (270 MHz, CDCl₃) δ2.65-2.88 (2H, m), 3.40-3.48 (1H, m), 3.79-3.88 (1H, m), 3.79 and 3.83(3H, s), 3.88 (3H, s), 4.09-4.40 (1H, m), 4.84 (1H, s), 5.43 and 5.46(1H, s), 6.56-6.60 (1H, m), 6.67-6.73 (1H, m), 6.79-6.86 (1H, m),6.92-7.13 (3H, m); HRMS (ES+) calcd. for C₁₈H₁₉NO₄ (M⁺+H) 314.1387,found 314.1390; LC/MS (APCI) t_(r)=1.69 min, m/z 314.2 (M⁺+H); HPLCt_(r)=1.466 min (>98%).

B10 2-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 3,4-dimethoxybenzoic acid (301 mg, 1.65 mmol)were reacted as described for the synthesis of B2. Purification bycolumn chromatography afforded B10 (345 mg, 73%). m.p. 58-77° C.; R_(f):0.16 (1:2, petrol:ethyl acetate); ¹H NMR (270 MHz, CDCl₃) δ 2.85 (2H, brs), 3.75-3.95 (2H, br m), 3.87 (3H, s), 3.91 (3H, s), 4.72 (2H, br s),5.15 (1H, s), 6.63-6.69 (2H, m), 6.86 (1H, d, J=8.5), 7.01-7.04 (2H, m);HRMS (ESI+) calcd. for C₁₈H₂₀NO₄ (M⁺+H) 314.1387, found 314.1395; LC/MS(ES+) t_(r)=1.40 min, m/z 314.4 (M⁺+H); HPLC t_(r)=1.587 min (>98%).

B11 2-(2,4,5-Trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 2,4,5-trimethoxybenzoic acid (350 mg, 1.65mmol) were reacted as described for the synthesis of B2. Purification bycolumn chromatography afforded B11 (222 mg, 45%). m.p. 180-188° C.; ¹HNMR (270 MHz, CDCl₃) δ 2.62-2.76 (1H, m), 2.77-2.86 (2H, m), 3.43-3.51(1H, m), 3.68 and 3.74 (3H, s), 3.77 and 3.78 (3H, s), 3.89 (3H, s),4.03-4.14 (1H, m), 4.25-4.45 (1H, m), 4.79 (1H, s), 6.49 (1H, d, J=3.9),6.55-6.62 (1H, m), 6.60 and 6.93 (1H, d, J=8.3), 6.65-6.67 (1H, m), 6.80(1H, d, J=7.2), 7.35 (1H, s); HRMS (ESI+) calcd. for C₁₉H₂₂NO₅ (M⁺+H)344.1492, found 344.1477; LC/MS (ES+) t_(r)=1.70 min (>?%), m/z 344.3(M⁺+H); HPLC t_(r)=1.412 min (>99.5%).

B12 2-(3,5-Dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 3,5-dimethoxybenzoyl chloride (331 mg, 1.65mmol) were dissolved in DCM (10 mL) and cooled to 0° C. Triethylamine(627 μL, 4.5 mmol) and the solution stirred for 30 minutes prior towarming to room temperature and stirring for 18 hours. The resultantsolution was diluted with DCM and washed with NaHCO₃ (sat.) and brine,dried over MgSO₄ filtered and solvent evaporated under reduced pressure.Purification by column chromatography afforded B12 (146 mg, 31%). ¹H NMR(270 MHz, CDCl₃) δ 2.74-2.85 (2H, m), 3.58 and 3.91 (2H, m), 3.77 (3H,s), 4.48 and 4.77 (2H, s), 6.49-6.71 (5H, m), 6.72 and 6.98 (1H, d,J=7.7); HRMS (ESI+) calcd. for C₁₈H₂₀NO₄ (M⁺+H) 314.1387, found314.1378; LC/MS (ES+) t_(r)=2.09 min (>?%), m/z 314.3 (M⁺+H); HPLCt_(r)=1.476 min (>99%).

B13 2-(2,4,6-Trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 2,4,6-trimethoxybenzoic acid (350 mg, 1.65mmol) were reacted as described for the synthesis of B2. Purification bycolumn chromatography afforded B13 (308 mg, 62%). ¹H NMR (270 MHz,MeOD-d₄) δ 2.71 and 2.85 (2H, t, J=5.2), 3.45 and 3.87 (2H, t, J=6.1),3.67 (3H, d, J=1.3), 3.78 (3H, d, J=1.3), 3.84 (3H, t, J=1.3), 4.30 and4.73 (2H, s), 6.26 (2H, dd, J=8.0, 1.3), 6.54-6.67 (2H, m), 6.73 and7.01 (1H, d, J=8.3); HRMS (ESI+) calcd. for C₁₉H₂₂NO₅ (M⁺+H) 344.1492,found 311.1479; LC/MS (ES+) t_(r)=1.95 min (>?%), m/z 344.3 (M⁺+H); HPLCt_(r)=1.423 min (>99%)

B14 2-(3,4,5-Triethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (690 mg, 3 mmol) and 3,4,5-triethoxybenzoic acid (1.14 g, 4.5 mmol)were reacted as described for the synthesis of B2. Purification bycolumn chromatography afforded B142-(3,4,5-Triethoxybenzoyl)-1,2,3,4-tetrahydroisoquinolin-6-ol in 63%(731 mg) m.p. 158° C.; ¹H NMR (270 MHz, CDCl₃) δ 1.32-1.42 (9H, m), 2.80(2H, br s), 3.62 and 3.92 (2H, br s), 3.98-4.11 (6H, m), 4.51 and 4.75(2H, br s), 5.97 (1H, br s), 6.62-6.66 (4H, m), 6.67 and 7.00 (1H, brs); HRMS (ESI+) calcd. for C₂₂H₂₈NO₅ (M⁺+H) 386.1962, found 386.1960;LC/MS (APCI) t_(r)=1.69 min, m/z 386.5 (M⁺+H); HPLC t_(r)=1.663 min(>97%).

In addition phenolic ester B142-(3,4,5-Triethoxybenzoyl)-6-O-(3,4,5-triethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline94 mg was also isolated and showed ¹H NMR (270 MHz, CDCl₃) δ 1.32-1.48(18H, m), 2.92 (2H, br s), 3.68 and 4.05 (2H, br s), 4.01-4.19 (12H, m),4.64 and 4.83 (2H, br s), 6.62 (2H, s), 6.95 and 7.21 (1H, m), 7.00 (2H,app s), 7.38 (2H, s); HRMS (ESI+) calcd. for C₃₅H₄₄NO₉ (M⁺+H) 622.3011,found 622.3004; LC/MS (APCI) t_(r)=3.69 min, m/z 622.1 (M⁺+H); HPLCt_(r)=3.555 min (>85%)

B15 Benzylation of 6-methoxytetrahydroisoquinoline hydrochloride

A microwave tube (10 mL) was charged with6-methoxytetrahydroisoquinoline hydrochloride (300 mg, 1.5 mmol),3,4,5-trimethoxybenzylchloride (325 mg, 1.5 mmol), triethylamine (0.5mL, 3.6 mmol) dissolved in ethanol (5 mL) and sealed. The Vial washeated to 120° C. with 150 W for 60 minutes. After cooling to roomtemperature the solution was dissolved in ethyl acetate and washed withwater (2×10 mL), brine (10 mL), dried over MgSO₄ and evaporated todryness in vacuo. Purification by flash column chromatography on aflashmaster system (1:0-1:1 petrol 40-60:ethylacetate) afforded thedesired compound in 16% yield (81 mg) and >97% purity as a soft solid.m.p. 102-103° C.; ¹H NMR (270 MHz, CDCl₃) δ 2.69 (2H, d, J=7.8), 2.87(2H, t, J=7.8), 3.58 (2H, s), 3.59 (2H, s), 3.77 (3H, s), 3.84 (3H, s),3.85 (6H, s), 6.62-6.71 (4H, m), 6.92 (1H, d, J=8.2); HRMS (ESI+) calcd.for C₂₀H₂₆NO₄ (M⁺+H) 344.1856, found 344.1842; LC/MS (ES+) t_(r)=2.165min, m/z 344.4 (M⁺+H); HPLC t_(r)=2.47 min (>97%).

B16 2-(2-Methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

A solution of B1 (345 mg, 1.5 mmol), and 2-methoxybenzyl chloride (230μL, 1.65 mmol) in DMF (10 mL) was treated with Huning's base (1.82 mL,10.5 mmol) and heated to 80° C. for 60 h. After cooling to roomtemperature, water (5 mL) was added and the product extracted with ethylacetate (4×10 mL). The combined organics were washed with water, brineand dried over MgSO₄, prior to evaporation and purification by flashcolumn chromatography. B16 was isolated as a white solid in 85% yield(345 mg). m.p. 148-155° C.; R_(f): 0.23 (1:1 Petrol:ethyl acetate) ¹HNMR (270 MHz, CDCl₃) δ 2.66-2.70 (2H, m), 2.73-2.76 (2H, m), 3.59 (2H,br s), 3.74 (2H, br s), 3.75 (3H, s), 6.20 (1H, d, J=2.43), 6.39 (1H,dd, J=2.7, 9.2), 6.73 (1H, d, J=9.2) 6.83-6.92 (2H, m), 7.24 (1H, dt,J=1.6, 8.1), 7.36 (1H, dd, J=1.4, 8.1); HRMS (ES+) calcd. for C₁₇H₂₀NO₂(M⁺+H) 270.1489, found 270.1478; LC/MS (ES+) t_(r)=1.92 min, m/z 270.4(M⁺+H); HPLC t_(r)=2.917 min (>98%).

B17 2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 4-methoxybenzyl bromide (238 μL, 1.65 mmol)were reacted as described for the synthesis of B16. Purification byflash column chromatography gave B17 as a tan solid in 61% yield (246mg). m.p. 158-160° C.; ¹H NMR (270 MHz, CDCl₃) δ 3.65-3.75 (4H, m), 3.52(2H, s), 3.63 (2H, m), 3.78 (5H, app s), 6.21 (1H, d, J=2.2), 6.43 (1H,dd, J=8.3, 2.2), 6.72 (1H, d, J=8.3), 6.85 (2H, d, J=8.5), 7.29 (2H, d,J=8.5); HRMS (ESI+) calcd. for C₁₇H_(2O)NO₂ (M⁺+H) 270.1489, found270.1477; LC/MS (APCI) t_(r)=1.77 min (>?%), m/z 270.3 (M⁺+H); HPLCt_(r)=2.952 min (>97%)

B18 2-(3-Ethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B4 (200 mg, 0.67 mmol) was dissolved in THF (2 mL) and addeddropwise to a stirred suspension of lithium aluminium hydride (127 mg,3.4 mmol) in THF (5 mL) cooled in an ice bath. The resultant mixture wasstirred for 30 mins at 0° C. and then allowed to warm to roomtemperature overnight. The solution was then cooled in an ice bath andquenched with by the slow addition of ethyl acetate (10 mL) and left tostand for 30 mins. Solids were removed by filtration through a Celite®plug and solvent removed in vacuo. The crude product was purified byflash column chromatography to afford B18 as a white solid (75 mg, 38%).m.p. 120-121° C.; ¹H NMR (400 MHz, CDCl₃) δ 1.38 (3H, t, J=7.2), 2.73(4H, app s), 3.56 (2H, s), 3.67 (2H, s), 3.98 (2H, q, J=7.2), 6.32 (1H,d, J=2.4), 6.49 (1H, dd, J=8.4, 2.4), 6.77 (1H, d, J=8.0), 6.82 (1H, dd,J=8.0, 2.4), 6.94-6.98 (2H, m), 7.23 (1H, t, J=8.0); ¹³C NMR (100 MHz,CDCl₃) δ 14.81 (CH₃), 28.60 (CH₂), 50.51 (CH₂), 55.30 (CH₂), 62.74(CH₂), 63.28 (CH₂), 113.60 (CH), 113.67 (CH), 115.11 (CH), 115.18 (CH),121.73 (CH), 125.65 (C), 127.54 (CH), 129.22(CH), 135.12 (C), 138.77(C),154.56 (C), 158.98 (C); HRMS (ESI+) calcd. for C₁₈H₂₂NO₂ (M⁺+H)284.1645, found 284.1632; HPLC t_(r)=2.234 min (>97%)

B19 2-(2,5-Dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 2-methoxybenzyl chloride (308 mg, 1.65 mmol)were reacted as described for the synthesis of B16. Purification bycrystallisation from ethanol gave B19 as an off white solid in 73% yield(327 mg). m.p. 178-192° C. ¹H NMR (270 MHz, CDCl₃) δ 2.77-2.83 (4H, m),3.59 (2H, s), 3.71 (2H, s), 3.75 (3H, s), 3.79 (3H, s), 6.52-6.56 (2H,m), 6.81-6.98 (4H, m); HRMS (ES+) calcd. for C₁₈H₂₂NO₃ (M⁺+H) 300.1594,found 300.1580; LC/MS (APCI) t_(r)=0.83 min, m/z 300.4 (M⁺+H); HPLCt_(r)=1.303 min (>99.9%)

B20 2-(3,5-Dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

B1 (345 mg, 1.5 mmol) and 3,5-methoxybenzyl chloride (308 mg, 1.65 mmol)were reacted as described for the synthesis of B16. Purification bycrystallisation from ethanol gave B20 as an off white solid in 19% yield(85 mg). m.p. 189-195° C. ¹H NMR (270 MHz, MeOD-d₄) δ 2.68-2.73 (2H, m),2.21-2.86 (2H, m), 3.52 (2H, s), 3.60 (2H, s), 3.76 (3H, s), 3.77 (3H,s), 3.39 (1H, m), 6.53-6.57 (4H, m), 6.82 (1H, d, J=8.0); HRMS (ES+)calcd. for C₁₈H₂₂NO₃ (M⁺+X) 300.1594, found 300.1582; LC/MS (APCI)t_(r)=0.78 min, m/z 300.2 (M⁺+H); HPLC t_(r)=1.098 min (>99.9%).

B21 2-(2,3-Dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B9 (163 mg, 0.52 mmol) in THF (5 mL), was added slowly to acooled stirred suspension of LiAlH₄ (99 mg, 2.6 mmol) in THF (3 mL).After warming to room temperature the suspension was stirred for 18hours before being cooled to 0° C. Water (99 μL) was added slowlyfollowed by 15% NaOH (99 μL) then water (297 μL). The solution wasallowed to warm to room temperature and stirred for 15 minutes. Thethick suspension was diluted with ethyl acetate and MgSO₄ added. Theresulting mixture was stirred for a further 15 minutes then filtered toremove the salts, evaporated to dryness and purified by flash columnchromatography to afford the desired product as a colourless solid, (136mg, 87%). m.p. 111-115° C.; ¹H NMR (270 MHz, CDCl₃) δ 2.70-2.74 (4H, m),3.58 (2H, s), 3.76 (2H, s), 3.82 (3H, s), 3.86 (3H, s), 6.27 (1H, d,J=2.2), 6.45 (1H, dd, J=2.2, 8.3), 6.74 (1H, d, J=8.3), 6.83 (1H, dd,J=1.7, 7.7), 6.97-7.06 (2H, m); ¹³C NMR (100 MHz, CDCl₃) δ 8.7(CH₂),50.4(CH₂), 55.0(CH₂), 55.6(CH₂), 55.7(CH₃), 60.8(CH₃), 111.3(CH),113.5(CH), 115.1(CH), 122.9(CH), 123.8(CH), 125.8(C), 127.4(CH),130.9(C), 135.1(C), 147.8(C), 152.6(C), 154.5(C); HRMS (ESI+) calcd. forC₁₈H₂₂NO₃ (M⁺+H) 300.1594, found 300.1581; LC/MS (ES+) t_(r)=2.15 min,m/z 300.3 (M⁺+H); HPLC t_(r)=2.346 min (>97%)

B22 2-(3,4-Diethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B6 (240 mg, 0.7 mmol) in THF (5 mL), was added slowly to acooled stirred suspension of LiAlH₄ (133 mg, 3.5 mmol) in THF (3 mL).After warming to room temperature the suspension was stirred for 18hours before being cooled to 0° C. Water (133 μL) was added slowlyfollowed by 15% NaOH (133 μL) then water (399 μL). The solution wasallowed to warm to room temperature and stirred for 15 minutes. Thethick suspension was diluted with ethyl acetate and MgSO₄ added. Theresulting mixture was stirred for a further 15 minutes then filtered toremove the salts, evaporated to dryness and purified by flash columnchromatography to afford the desired product as a colourless solid, (103mg, 45%). m.p. 150-154° C.; ¹H NMR (270 MHz, CDCl₃) δ 1.35 (3H, t,J=6.9), 1.42 (3H, t, J=6.9), 2.67 (4H, s), 3.50 (2H, s), 3.59 (2H, s),3.95 (2H, q, J=6.9), 4.04 (2H, q, J=6.9), 6.21 (1H, d, J=1.7), 6.43 (1H,dd, J=2.5, 8.3), 6.73 (1H, d, J=8.3), 6.77-6.85 (2H, m); HRMS (ESI+)calcd. for C₂₀H₂₆NO₃ (M⁺+H) 328.1907, found 328.1892; LC/MS (ES+)t_(r)=2.22 min, m/z 328.3 (M⁺+H); HPLC t_(r)=2.519 min (>99%).

B23 2-(3,4-Dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B10 (210 mg, 0.67 mmol) in THF (5 mL), was added slowly to acooled stirred suspension of LiAlH₄ (127 mg, 3.35 mmol) in THF (3 mL).Reaction and work up as B22, flash column chromatography gave B23 as acolourless solid, (127 mg, 64%). m.p. 119-122° C.; ¹H NMR (270 MHz,CDCl₃) δ 2.67-2.70 (4H, m), 3.50 (2H, s), 3.60 (2H, s), 3.74 (3H, s),3.85 (3H, s), 6.19 (1H, d, J=2.2), 6.42 (1H, dd, J=2.2, 8.3), 6.71-6.87(3H, m), 6.99 (1H, d, J=1.4); ¹³C NMR (100 MHz, CDCl₃) δ 28.5(CH₂),50.4(CH₂), 55.3(CH₂), 55.7(CH₃), 55.8(CH₃), 62.5(CH₂), 110.6(CH),112.5(CH), 113.6(CH), 115.1(CH), 121.7(CH), 125.5(C), 127.5(CH),129.8(C), 135.1(C), 148.2(C), 148.9(C), 154.7(C); HRMS (ESI+) calcd. forC₁₈H₂₂NO₃ (M⁺+H) 300.1594, found 300.1582; LC/MS (ES+) t_(r)=1.89 min,m/z 300.3 (M⁺+H); HPLC t_(r)=2.157 min (>97%)

B242-(Benzo[d][1,3]dioxol-5-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B2 (160 mg, 0.54 mmol) in THF (5 mL), was added slowly to acooled stirred suspension of LiAlH₄ (102 mg, 2.69 mmol) in THF (3 mL).After warming to room temperature the suspension was stirred for 18hours before being cooled to 0° C. Water (102 μL) was added slowlyfollowed by 15% NaOH (102 μL) then water (306 μL). The solution wasallowed to warm to room temperature and stirred for 15 minutes. Thethick suspension was diluted with ethyl acetate and MgSO₄ added. Theresulting mixture was stirred for a further 15 minutes then filtered toremove the salts, evaporated to dryness and purified by flash columnchromatography to afford B24 as a colourless solid (89 mg, 59%). m.p.169-172° C.; ¹H NMR (270 MHz, MeOD-d₄) δ 2.69 (2H, app t, J=6.0), 2.81(2H, app t, J=6.0), 3.50 (2H, s), 3.58 (2H, s), 5.92 (2H, s), 6.53-6.57(2H, m), 6.78-6.83 (3H, m), 6.90 (1H, s); ¹³C NMR (100 MHz, CDCl₃) δ29.6 (CH₂), 51.4 (CH₂), 56.5 (CH₂), 63.4 (CH₂), 102.3 (CH₂), 108.8 (CH),110.9 (CH), 114.4 (CH), 115.6 (CH), 124.2 (CH), 126.3 (C), 128.5 (CH),132.1 (C), 136.2 (C), 148.5 (C), 149.2 (C), 156.9 (C); HRMS (ESI+)calcd. for C₁₇H₁₈NO₃ (M⁺+H) 284.1281, found 284.1275; LC/MS (ES+)t_(r)=2.15 min, m/z 284.2 (M⁺+H); HPLC t_(r)=2.066 min (>96.6%).

B25 2-(2,4-Dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B8 (200 mg, 0.64 mmol) in THF (5 mL), was added slowly to acooled stirred suspension of LiAlH₄ (121 mg, 3.2 mmol) in THF (3 mL).After warming to room temperature the suspension was stirred for 18hours before being cooled to 0° C. Water (121 μL) was added slowlyfollowed by 15% NaOH (121 μL) then water (363 μL). The solution wasallowed to warm to room temperature and stirred for 15 minutes. Thethick suspension was diluted with ethyl acetate and MgSO₄ added. Theresulting mixture was stirred for a further 15 minutes then filtered toremove the salts, evaporated to dryness and purified byrecrystallisation from hot methanol to afford the B25 as a colourlesssolid, (92 mg, 48%). m.p. 149-152° C.; ¹H NMR (270 MHz, MeOD-d₄) δ2.72-2.75 (2H, m), 2.80-2.83 (2H, m), 3.55 (2H, s), 3.66 (2H, s), 3.80(3H, s), 3.82 (3H, s), 6.49-6.56 (4H, m), 6.82 (1H, d, J=8.4), 7.22 (1H,d, J=8.4); ¹³C NMR (100 MHz, MeOD-d₄) δ 29.6 (CH₂), 49.2 (CH₃), 51.4(CH₂), 55.8 (CH₃), 56.2 (CH₂), 56.3 (CH₂), 99.2 (CH), 105.4 (CH), 114.3(CH), 115.6 (CH), 118.0, 126.5, 128.5 (CH), 133.4 (CH), 136.2, 156.2,156.8, 160.6, 162.2; HRMS (ESI+) calcd. for C₁₈H₂₂NO₃ (M⁺+H) 300.1594,found 300.1984; LC/MS (ES+) t_(r)=0.77 min, m/z 300.2 (M⁺+H); HPLCt_(r)=1.047 min (>99.15%)

B26 2-(2,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B11 (55 mg, 0.16 mmol) in THF (5 mL), was added slowly to acooled stirred suspension of LiAlH₄ (86 mg, 2.6 mmol) in THF (3 mL).After warming to room temperature the suspension was stirred for 18hours before being cooled to 0° C. Water (86 μL) was added slowlyfollowed by 15% NaOH (86 μL) then water (258 μL). The solution wasallowed to warm to room temperature and stirred for 15 minutes. Thethick suspension was diluted with ethyl acetate and MgSO₄ added. Theresulting mixture was stirred for a further 15 minutes then filtered toremove the salts, evaporated to dryness and purified by flash columnchromatography and recrystallisation from hot methanol to afford B26 asa colourless solid, (29 mg, 56%). m.p. 188-191° C.; ¹H NMR (270 MHz,CDCl₃) δ 2.68-2.78 (4H, m), 3.58 (2H, s), 3.64 (2H, s), 3.80 (6H, s),3.88 (3H, s), 6.44-6.45 (1H, m), 6.52-6.55 (2H, m), 6.83 (1H, d, J=8.0),6.99 (1H, s); HRMS (ESI+) calcd. for C₁₉H₂₄NO₄ (M⁺+H) 330.1700, found330.1688; LC/MS (ES+) t_(r)=0.76 min, m/z 330.3 (M⁺+H); HPLC t_(r)=1.025min (>99.21%).

B27 2-(3,4,5-triethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B14 (258 mg, 0.67 mmol) was dissolved in THF (2 mL) and addeddropwise to a stirred suspension of lithium aluminium hydride (127 mg,3.4 mmol) in THF (5 mL) cooled in an ice bath. The resultant mixture wasstirred for 30 mins at 0° C. and then allowed to warm to roomtemperature overnight. After which time the solution was cooled in anice bath and quenched with by the slow addition of ethylacetate (10 mL)and left to stand for 30 mins. Solids were removed by filtration througha Celite plug and solvent removed in vacuo. The crude product waspurified by flash column chromatography to afford B27 as a white solid(75 mg, 38%). m.p. 140-142° C.; ¹H NMR (400 MHz, CDCl₃) δ 1.34 (3H, t,J=7.2), 1.35 (3H, t, J=6.8), 2.68 (4H, s), 3.52 (2H, s), 3.57 (2H, s),3.97 (2H, q, J=6.8), 4.04 (2H, q, J=7.2), 6.27 (1H, d, J=2.4), 6.45 (1H,dd, J=8.4, 2.4), 6.59 (2H, s), 6.75 (1H, d, J=8.4); ¹³C NMR (100 MHz,CDCl₃) δ 14.91 (CH₃), 15.57 (CH₃), 28.57 (CH₂), 50.46 (CH₂), 55.40(CH₂), 63.01 (CH₂), 64.48 (CH₂), 68.81 (CH₂), 107.74 (CH), 113.58 (CH),115.05 (CH), 127.52 (CH), 132.60 (C), 135.09 (C), 136.79 (C), 152.70(C), 154.70 (C); HRMS (ESI+) calcd. for C₂₂H₃₀NO₄ (M⁺+H) 372.2169, found372.2156; HPLC t_(r)=2.501 min (>98%)

B28 2-(2-Hydroxy-4,6-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

Lithium aluminium hydride was added to a suspension of amide B13 inanhydrous dioxane under an atmosphere of nitrogen and stirred overnight.TLC showed little conversion so the reaction solution was heated to 110°C. for 4 hours. Upon cooling to 0° C. the solution was quenched withwater (395 μL), 15% sodium hydroxide solution (395 μL) and water (1.19mL). the solution was allowed to warm to room temperature and stirredfor 20 minutes, diluted with ethyl acetate and dried with MgSO₄. Afterstirring for an additional 20 minutes salts were removed my filtrationand the product crystallised from dichloromethane to afford B28, 130 mgof a white solid (20% yield). m.p. 109-112° C.; ¹H NMR (400 MHz,MeOD-d₄) δ 2.79-2.83 (4H, m), 3.62 (2H, s), 3.73 (3H, s), 3.75 (3H, s),3.84 (2H, s), 5.98 (1H, d, J=2.0), 6.06 (1H, d, J=2.4), 6.54 (1H, d,J=2.0), 6.56 (1H, d, J=2.4), 6.58 (1H, d, J=2.0), 6.83 (1H, d, J=8.4);¹³C NMR (100 MHz, CDCl₃) δ 29.7 (CH₂), 51.1 (CH₂), 53.7 (CH₂), 55.57 and55.61 (CH₃), 55.8 (CH₂), 55.93 and 55.96 (CH₃), 90.9 (CH), 94.9 (CH),102.8 (C), 114.5 (CH), 115.7 (CH), 125.8 (C), 128.6 (CH), 135.8 (C),157.0 (C), 160.3 (C), 160.9 (C), 162.3 (C); HRMS (ESI+) calcd. forC₁₈H₂₂NO₄ (M⁺+H) 316.1543, found 316.1532; LC/MS (ES+) t_(r)=0.78 min,m/z 316.4 (M⁺+H); HPLC t_(r)=1.027 min (>99.4%).

B29 2-(3,4,5-Trimethoxyphenethyl)-1,2,3,4-tetrahydroisoquinolin-6-ol

The amide B5 (200 mg, 0.56 mmol) in THF (5 mL), was added slowly to acooled stirred suspension of LiAlH₄ (106 mg, 2.79 mmol) in THF (3 mL).After warming to room temperature the suspension was stirred for 18hours before being cooled to 0° C. Water (106 μL) was added slowlyfollowed by 15% NaOH (106 μL) then water (318 μL). The solution wasallowed to warm to room temperature and stirred for 15 minutes. Thethick suspension was diluted with ethyl acetate and MgSO₄ added. Theresulting mixture was stirred for a further 15 minutes then filtered toremove the salts, evaporated to dryness and purified by flash columnchromatography to afford B29 as a colourless solid, (120 mg, 63%). m.p.180-186° C.; ¹H NMR (270 MHz, CDCl₃) δ 2.72-2.87 (4H, m), 3.64 (2H, s),3.82 (3H, s), 3.84 (6H, s), 6.44 (2H, s), 6.54 (1H, d, J=2.5), 6.59 (1H,dd, J=2.5, 8.3), 6.89 (1H, d, J=8.3), 7.25 (1H, s); ¹³C NMR (100 MHz,CDCl₃) δ 28.7 (CH₂), 34.0 (CH₂), 51.0 (CH₂), 55.4 (CH₂), 56.1 (CH₃),60.2 (CH₂), 60.8(CH₃), 105.6 (CH), 113.8 (CH), 115.2 (CH), 125.4 (C),127.6 (CH), 135.1 (C), 135.8 (C), 136.3 (C), 153.1 (C), 154.9 (C); HRMS(ESI+) calcd. for C₂₀H₂₆NO₄ (M⁺+H) 344.1856, found 344.1840; LC/MS (ES+)t_(r)=1.95 min, m/z 344.3 (M⁺+H); HPLC t_(r)=2.358 min (>98%).

C1 N-benzyl-4-(benzyloxy)-3-methoxybenzylamine

To a stirred solution of benzylamine (13.1 mL, 0.12 mol) and4-benzyloxy-3-methoxybenzaldehyde (24.2 g, 0.1 mol) in1,2-dichloroethane (50 mL) and chloroform (250 mL) was added sodiumtriacetoxyborohydride (31.79 g, 0.15 mol). The mixture was stirred atroom temperature for 18 hrs, saturated NaHCO₃ was added. The organicphase was separated and aqueous phase extracted with chloroform. Thecombined extracts were washed with brine, dried over MgSO₄ andevaporated to afford the crude product. Purification by flash columnchromatography afforded the title compound as a pale yellow oil in 76%yield (25.2 g). R_(f): 0.17 (petrol:ethyl acetate; 1:1). ¹H NMR (270MHz, CDCl₃) δ 3.73 (2H, s), 3.79 (2H, s), 3.89 (3H, s), 5.13 (2H, s),6.75-6.84 (2H, m), 6.91 (1H, d, J=1.4), 7.23-7.44 (10H, m); HRMS (ESI+)calcd. for C₂₂H₂₄NO₂ (M⁺+H) 334.1802, found 334.1787; LC/MS (ES+)t_(r)=1.19 min, m/z 334.5 (M⁺+H);

C3 N-Benzyl-3,4-dimethoxybenzylamine

To a stirred solution of benzylamine (3.94 mL, 36 mmol) and4,3-dimethoxybenzaldehyde (5.0 g, 30 mmol) in chloroform (120 mL), wasadded sodium triacetoxyborohydride (9.53 g, 45 mmol). The mixture wasstirred at rt for 18 hrs prior to addition of saturated NaHCO₃. Theorganic phase was separated and the aqueous phase extracted withchloroform. The combined extracts were washed with brine, dried overMgSO₄ and evaporated to afford the crude product. Purification by flashcolumn chromatography afforded the title compound as a pale yellow oil(5.47 g, 71%). ¹H NMR (270 MHz, CDCl₃) δ 3.74 (2H, s), 3.80 (2H, s),3.86 (3H, s), 3.88 (3H, s), 6.80-6.89 (3H, m), 7.22-7.34 (5H, m); HRMS(ESI+) calcd. for C₁₆H₂₀NO₂ (M⁺+H) 258.1489, found 258.1478; LC/MS (ES+)t_(r)=0.79 min, m/z 258.2 (M⁺+H).

C5 N-Benzyl-2-chloromethyl-4,5-dimethoxybenzylamine hydrochloride

Concentrated hydrochloric acid (22 mL) was added to a cooled solution ofbenzylamine C3 (2.72 g, 10.6 mmol) and paraformaldehyde (952 mg, 32mmol). The mixture was then heated to 50° C. for 16 hours after whichthe solvent was removed under reduced pressure. Acetone 10 mL was addedto the residue and left to stand overnight. Crystals were removed byfiltration and dried to afford 3.05 g (84%). ¹H NMR (270 MHz, CDCl₃) δ3.72 (3H, s), 3.78-3.89 (4H, m), 3.93 (3H, s), 4.35 (2H, s), 6.69 (1H,s), 7.33-7.40 (4H, m), 7.46-7.50 (2H, m), 10.20 (2H, br s).

C7 2-Benzyl-5,6-dimethoxyisoindoline

The amine salt C5 (1.67 g, 4.88 mmol) was added to a suspension of K₂CO₃(1.71 g, 12.4 mmol) in toluene (30 mL) and stirred at room temperatureovernight. TLC showed little reaction had occurred so chloroform (30 mL)was added and the solution heated at 50° C. for 16 hours. The solutionwas filtered, solvent removed in vaccuo and purified by flash columnchromatography to afford 667 mg (51% yield) of the desired product. ¹HNMR (270 MHz, CDCl₃) δ 3.83 (6H, s), 3.88 (4H, s), 3.89 (2H, s), 6.71(2H, s), 7.26-7.42 (5H, m); LC/MS (ES+) t_(r)=0.81 min, m/z 270.2(M⁺+H).

C8 2-Benzyl-5,6-dimethoxyisoindoline

A CEM microwave tube was charged with a mixture of the HCl salt C5 (150mg, 0.44 mmol), triethylamine (305 μL, 2.2 mmol), in ethanol and heatedat 120° C. (150 W) for 10 minutes. TLC showed little conversion and thereaction reheated at 120° C. for 60 mins. The solution was diluted withwater and the product extracted into ethylacetate (×3) and the combinedorganics dried with brine and MgSO₄. purification of the crude productby flash column chromatography afford the desired compound in 74% yieldas a white solid which darkens over time. R_(f): 0.41 (1:1petrol:ethylacetate);

¹H NMR (270 MHz, CDCl₃) δ 3.83 (6H, s), 3.88 (4H, s), 3.89 (2H, s), 6.71(2H, s), 7.26-7.42 (5H, m); HRMS (ESI+) calcd. for C₁₇H₂₀NO₂, (M⁺+H)270.1489, found 270.1479; LC/MS (ES+) t_(r)=0.81 min, m/z 270.2 (M⁺+H).

Biological Data

The following biological data were obtained using the Protocolsdescribed herein.

Antiproliferative assays. DU145 cells were seeded into 96 wellmicrotiter plates (5000 cells/well) and treated with 10⁹ to 10⁴ M ofcompounds or with vehicle control. At 96 hours post-treatment, live cellcounts were determined by WST-1 cell proliferation assay (Roche,Penzberg, Germany), as per manufacturer's instructions. Viabilityresults were expressed as a percentage of mean control values resultingin the calculation of the 50% growth inhibition (GI50). All experimentswere performed in triplicate.

Cmp DU-145 No. R₁ A G B R₄ R₅ R₆ R₇ R₈ GI₅₀ μM 2 Bn CH₂ CH₂ CH₂ H H H HH 50 to 100 3 Bn CH₂ CH₂ CH₂ H H OMe H H 50 to 100 4 Bn CH₂ CH₂ CH₂ HOMe H H H 50 to 100 5 Bn CH₂ CH₂ CH₂ OMe H H H H 10 to 50  6 Bn CH₂ CH₂CH₂ H OMe H OMe H >100 7 Bn CH₂ CH₂ CH₂ H Me H H H >100 8 Bn CH₂ CH₂ CH₂H OPh H H H >100 16 Bn CH₂ CH₂ CH₂ OMe OMe OMe H H NT 17 Bn CH₂ CH₂ CH₂OMe H OMe OMe H 10 to 50  19 Bn CH₂ CH₂ CH₂ H OMe OMe H H 10 to 50  20Bn CH₂ CH₂ CH₂ OMe OMe H H H 10 to 50  21 Bn CH₂ CH₂ CH₂ OMe H H OMe H10 to 50  22 Bn CH₂ CH₂ CH₂ H F H H H >100 30 Bn CH₂ CH₂ CH₂ H OH H H HNA 34 Bn CH₂ CH₂ CH₂ H NH₂ H H H >100 38 H CH₂ CH₂ CH₂ H H H H H >100 39H CH₂ CH₂ CH₂ H H OMe H H >100 40 H CH₂ CH₂ CH₂ H OMe H H H >100 41 HCH₂ CH₂ CH₂ OMe H H H H >100 42 H CH₂ CH₂ CH₂ H OMe H OMe H 50 to 100 43H CH₂ CH₂ CH₂ H OPh H H H 10 to 50  44 H CH₂ CH₂ CH₂ H Me H H H >100 50H CH₂ CH₂ CH₂ H NHAc H H H >100 51 H CH₂ CH₂ CH₂ H OAc H H H NT 54 H CH₂CH₂ CH₂ H OMe OMe OMe H <10 55 H CH₂ CH₂ CH₂ OMe H H OMe H 50 to 100 56H CH₂ CH₂ CH₂ OMe OMe H H H >100 57 H CH₂ CH₂ CH₂ H OMe OMe H H >100 58H CH₂ CH₂ CH₂ OMe OMe OMe H H >100 59 H CH₂ CH₂ CH₂ OMe H OMe OMe H <1060 H CH₂ CH₂ CH₂ H F H H H >100 61 H CH₂ CH₂ CH₂ H O-i-Pr H H H >100 63H CH₂ CH₂ CH₂ H OEt H H H >100 64 H CH₂ CH₂ CH₂ H CN H H H >100 65 H CH₂CH₂ CH₂ H H CN H H >100 66 H CH₂ CH₂ CH₂ H NO₂ H H H >100 67 H CH₂ CH₂CH₂ H Cl H H H 50 to 100 68 H CH₂ CH₂ CH₂ H OCF₃ H H H 50 to 100 69 HCH₂ CH₂ CH₂ OH H H H H >100 70 H CH₂ CH₂ CH₂ H OH H H H >100 72 SO₂NH₂CH₂ CH₂ CH₂ H OMe H H H <10 73 SO₂NH₂ CH₂ CH₂ CH₂ H H OMe H H 50 to 10074 SO₂NH₂ CH₂ CH₂ CH₂ H H H H H 50 to 100 75 SO₂NH₂ CH₂ CH₂ CH₂ OMe H HH H <10 76 SO₂NH₂ CH₂ CH₂ CH₂ H OMe H OMe H <10 77 SO₂NH₂ CH₂ CH₂ CH₂ HMe H H H 10 to 50  78 SO₂NH₂ CH₂ CH₂ CH₂ H OPh H H H 10 to 50  79 SO₂NH₂CH₂ CH₂ CH₂ H OSO₂NH₂ H H H 10 to 50  80 SO₂NH₂ CH₂ CH₂ CH₂ H OEt H H H<10 82 SO₂NH₂ CH₂ CH₂ CH₂ H Ac H H H <10 85 SO₂NH₂ CH₂ CH₂ CH₂ H NHAc HH H >100 87 SO₂NH₂ CH₂ CH₂ CH₂ H OAc H H H 50 to 100 90 SO₂NH₂ CH₂ CH₂CH₂ H OMe OMe OMe H <10 91 SO₂NH₂ CH₂ CH₂ CH₂ OMe OMe H H H <10 92SO₂NH₂ CH₂ CH₂ CH₂ H OMe OMe H H <10 93 SO₂NH₂ CH₂ CH₂ CH₂ OMe OMe OMe HH 10 to 50  94 SO₂NH₂ CH₂ CH₂ CH₂ OMe H H OMe H <10 95 SO₂NH₂ CH₂ CH₂CH₂ OMe H OMe OMe H <10 97 SO₂NH₂ CH₂ CH₂ CH₂ H OH H H H 50 to 100 98SO₂NH₂ CH₂ CH₂ CH₂ H ON H H H NA 99 SO₂NH₂ CH₂ CH₂ CH₂ H H CN H H 50 to100 100 SO₂NH₂ CH₂ CH₂ CH₂ H NO₂ H H H <10 101 SO₂NH₂ CH₂ CH₂ CH₂ H Cl HH H <10 102 SO₂NH₂ CH₂ CH₂ CH₂ H OCF₃ H H H <10 104 SO₂NH₂ CH₂ CH₂ CH₂ HO-i-Pr H H H <10 108 Bn CH₂ CH₂ CO H H OMe H H 10 to 50  109 Bn CH₂ CH₂CO H OMe OMe H H 10 to 50  110 Bn CH₂ CH₂ CO H OMe H OMe H 10 to 50  115H CH₂ CH₂ CO OMe H H H H 50 to 100 116 H CH₂ CH₂ CO H OMe H H H 10 to50  117 H CH₂ CH₂ CO H H OMe H H >100 118 H CH₂ CH₂ CO H OMe OMe HH >100 119 H CH₂ CH₂ CO H OMe H OMe H <10 120 H CH₂ CH₂ CO H OMe OMe OMeH <10 122 SO₂NH₂ CH₂ CH₂ CO OMe H H H H 10 to 50  123 SO₂NH₂ CH₂ CH₂ COH OMe H H H <10 124 SO₂NH₂ CH₂ CH₂ CO H H OMe H H <10 125 SO₂NH₂ CH₂ CH₂CO H OMe OMe H H >100 125 SO₂NH₂ CH₂ CH₂ CO H OMe H OMe H <10 127 SO₂NH₂CH₂ CH₂ CO H OMe OMe OMe H <10 128 Bn CO CH₂ CO H H OMe H H >100 129 BnCO CH₂ CO H OMe H OMe H >100 130 Bn CO CH₂ CO OMe H H H H >100 131 Bn COCH₂ CO H OMe H H H NA 133 Bn CO CH₂ CO H OMe OMe H H >100 134 Bn CO CH₂CO H OMe OMe OMe H >100 135 Bn CO CH₂ CO H CN H H H >100 136 Bn CO CH₂CO H H CN H H >100 138 H CO CH₂ CO OMe H H H H <10 139 H CO CH₂ CO H OMeH H H <10 140 H CO CH₂ CO H H OMe H H >100 141 H CO CH₂ CO H OMe H OMe H<10 142 H CO CH₂ CO H OMe OMe H H <10 143 H CO CH₂ CO H OMe OMe OMe H<10 144 H CO CH₂ CO H CN H H H 50 to 100 145 H CO CH₂ CO H H CN H H >100147 SO₂NH₂ CO CH₂ CO H H OMe H H >100 148 SO₂NH₂ CO CH₂ CO OMe H H H H<10 149 SO₂NH₂ CO CH₂ CO H OMe H H H <10 150 SO₂NH₂ CO CH₂ CO H OMe HOMe H <10 151 SO₂NH₂ CO CH₂ CO H OMe OMe H H <10 152 SO₂NH₂ CO CH₂ CO HOMe OMe OMe H <10 153 SO₂NH₂ CO CH₂ CO H CN H H H 10 to 50  154 TIPS COCH₂ CH₂ H H OMe H H >100 155 3-MeOBn CO CH₂ CH₂ H OMe H H H >100 1562-MeOBn CO CH₂ CH₂ OMe H H H H >100 157 Bn CO CH₂ CH₂ H OMe H OMe H >100158 Bn CO CH₂ CH₂ H OMe OMe OMe H >100 159 H CO CH₂ CH₂ H H OMe H H >100160 H CO CH₂ CH₂ H OMe H H H >100 161 H CO CH₂ CH₂ OMe H H H H >100 162H CO CH₂ CH₂ H OMe H OMe H >100 163 H CO CH₂ CH₂ H OMe OMe OMe H >100164 SO₂NH₂ CO CH₂ CH₂ H H OMe H H >100 165 SO₂NH₂ CO CH₂ CH₂ OMe H H HH >100 166 SO₂NH₂ CO CH₂ CH₂ H OMe H H H >100 167 SO₂NH₂ CO CH₂ CH₂ HOMe H OMe H >100 168 SO₂NH₂ CO CH₂ CH₂ H OMe OMe OMe H >100 169 Bn CH₂CH₂ SO₂ H OMe H H H >100 170 Bn CH₂ CH₂ SO₂ H OCF₃ H H H >100 171 Bn CH₂CH₂ SO₂ H Me H H H >100 172 Bn CH₂ CH₂ SO₂ H CF₃ H H H >100 173 Bn CH₂CH₂ SO₂ H Cl H H H >100 174 Bn CH₂ CH₂ SO₂ H CN H H H >100 178 H CH₂ CH₂SO₂ H OMe H H H >100 179 H CH₂ CH₂ SO₂ H OCF₃ H H H >100 180 H CH₂ CH₂SO₂ H Me H H H >100 181 H CH₂ CH₂ SO₂ H CF₃ H H H >100 182 H CH₂ CH₂ SO₂H Cl H H H >100 183 H CH₂ CH₂ SO₂ CN H H H H >100 184 H CH₂ CH₂ SO₂ OMeH H H H >100 185 H CH₂ CH₂ SO₂ H H OMe H H >100 186 H CH₂ CH₂ SO₂ H CN HH H >100 187 SO₂NH₂ CH₂ CH₂ SO₂ H CN H H H >100 188 SO₂NH₂ CH₂ CH₂ SO₂ HOMe H H H 50 to 100 189 SO₂NH₂ CH₂ CH₂ SO₂ H CF₃ H H H 10 to 50  190SO₂NH₂ CH₂ CH₂ SO₂ H Cl H H H 10 to 50  191 SO₂NH₂ CH₂ CH₂ SO₂ H Me H HH 10 to 50  192 SO₂NH₂ CH₂ CH₂ SO₂ H OCF₃ H H H 50 to 100 193 SO₂NH₂ CH₂CH₂ SO₂ CN H H H H <10 194 SO₂NH₂ CH₂ CH₂ SO₂ OMe H H H H >100 195SO₂NH₂ CH₂ CH₂ SO₂ H H OMe H H >100 195 Bn CO CH₂ SO₂ H OMe H H H >100197 Bn CO CH₂ SO₂ OMe H H H H >100 199 Bn CO CH₂ SO₂ H Cl H H H >100 200H CO CH₂ SO₂ OMe H H H H >100 201 H CO CH₂ SO₂ H OMe H H H >100 202 H COCH₂ SO₂ H H OMe H H >100 203 H CO CH₂ SO₂ H Cl H H H >100 204 SO₂NH₂ COCH₂ SO₂ OMe H H H H >100 205 SO₂NH₂ CO CH₂ SO₂ H OMe H H H >100 206SO₂NH₂ CO CH₂ SO₂ H H OMe H H >100 207 SO₂NH₂ CO CH₂ SO₂ H Cl H H H >100217 H CH₂ CHMe CH₂ H OMe H H H <10 218 H CH₂ CHMe CH₂ H OMe H OMe H 10to 50  219 H CH₂ CHMe CH₂ H OMe OMe OMe H NA 220 SO₂NH₂ CH₂ CHMe CH₂ HOMe H H H <10 221 SO₂NH₂ CH₂ CHMe CH₂ H OMe H OMe H <10 222 SO₂NH₂ CH₂CHMe CH₂ H OMe OMe OMe H <10 228 H CH₂ CMe₂ CH₂ H OMe H H H NA 229 H CH₂CMe₂ CH₂ H OMe OMe OMe H NA 230 SO₂NH₂ CH₂ CMe₂ CH₂ H OMe H H H >100 231SO₂NH₂ CH₂ CMe₂ CH₂ H OMe OMe OMe H >100 234 H CH₂ CMe₂ CO H OMe OMe OMeH >100 236 H CH₂ CMe₂ CO H OMe H OMe H >100 236 SO₂NH₂ CH₂ CMe₂ CO H OMeOMe OMe H >100 237 SO₂NH₂ CH₂ CMe₂ CO H OMe H OMe H >100 SO₂Me CH₂ CH₂CH₂ H OMe OMe OMe H <10 Ac CH₂ CH₂ CH₂ H OMe OMe OMe H <10 Bn CH₂ CH₂CH₂ H OAc H H H 10 to 50  SO₂NH₂ CH₂ CH₂ CH₂ H F H H H 50 to 100 Bn CH₂CH₂ CH₂ H NHSO₂NH₂ H H H 50 to 100 Me CH₂ CH₂ CH₂ H OMe OMe OMe H >100Bn CH₂ CH₂ CH₂ H H CN H H >100 H CH₂ CH₂ CH₂ H NHSO₂NH₂ H H H >100SO₂NH₂ CH₂ CH₂ CH₂ H NHSO₂NH₂ H H H >100 Bn CH₂ CH₂ CH₂ H OMe OMe OMeH >100 SO₂NH₂ CH₂ CH₂ SO₂ CO₂Me H H H H 10 to 50  Bn CH₂ CH₂ SO₂ CO₂Me HH H H >100 H CH₂ CH₂ SO₂ CO₂Me H H H H >100 SO₂NH₂ CO CH₂ CO H H CN H HNA H CO CH₂ SO₂ CO₂Me H H H H >100 SO₂NH₂ CO CH₂ SO₂ CO₂Me H H H H >100

All publications and patents mentioned in the above specification areherein incorporated by reference.

Various modifications and variations of the present invention will beapparent to those skilled in the art without departing from the scopeand spirit of the invention. Although the invention has been describedin connection with specific preferred embodiments, it should beunderstood that the invention as claimed should not be unduly limited tosuch specific embodiments. Indeed, various modifications of thedescribed modes for carrying out the invention which are obvious tothose skilled in chemistry, biology or related fields are intended to bewithin the scope of the following claims.

1. A method of preventing or inhibiting tumor growth comprisingadministering a therapeutically effective amount of a compound to apatient in need thereof, wherein the compound is of Formula I or FormulaII

wherein A is —CR₁₀R₁₁, —S(═O)₂—, —NR₁₂—, or C═O, wherein R₁₀ and R₁₁independently represent —H, —OH, hydrocarbyl, —CN, —NO₂, or halogen, R₁₂is —H or hydrocarbyl; B is —(CR₁₃R₁₄)₁₋₃, C═O, CR₁₅R₁₆C═O, —S(═O)₂—,—NR₁₇— or —NR₁₈—C(═O)—, wherein each of R₁₃, R₁₄, R₁₅ and R₁₆independently represents H, —OH, hydrocarbyl, —CN, —NO₂, or halogen, R₁₇and R₁₈ independently represents H or hydrocarbyl; R₁ is —OH,O-hydrocarbyl, O-heterohydrocarbyl, —SO₂-hydrocarbyl, —CH═CH₂, halogen,—OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂, —NR₂₃—C(═O)H or —NR₃₅R₃₆ wherein each ofR₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₃₅ and R₃₆ independently represents H orhydrocarbyl; R₂ is —H, —O-hydrocarbyl, —S-hydrocarbyl, hydrocarbyl, —CN,—NO₂, or halogen, R₃ is

wherein each of R₄, R₅, R₆, R₇ and R₈ independently represents H, —OH,hydrocarbyl, —O-hydrocarbyl, —COOH, an ester of —COOH, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen, R₉ is —H or hydrocarbyl, and eachR₂₉ to R₃₃ independently represents H or hydrocarbyl; and wherein two ormore of R₄, R₅, R₆, R₇, R₈ and R₉ may together form a ring; wherein h isan optional bond, wherein G is CR₂₄R₂₅, wherein R₂₄ and R₂₅independently represent —H, —OH, hydrocarbyl, —CN, —NO₂, or halogen, orwherein when h is present G is CR₂₄, wherein R₂₄ is —H, —OH,hydrocarbyl, —CN, —NO₂, or halogen; n is 0, 1 or 2, each D independentlyrepresents —O, NR₂₆ or CR₂₇R₂₈, wherein each R₂₆ independentlyrepresents —H or hydrocarbyl; and each R₂₇ and R₂₈ independentlyrepresents —H, —OH, hydrocarbyl, —CN, —NO₂, or halogen; or salts of thecompound.
 2. The method of claim 1, wherein R₁ is —OH, O-hydrocarbyl,O-heterohydrocarbyl, —CH═CH₂, halogen, —OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂,—NR₂₃—C(═O)H or —NR₃₅R₃₆.
 3. The method of claim 1 wherein when R₁ is OHand R₃ is of Formula D, (i) at least one of R₄, R₅, R₆, R₇ and R₈independently represents halocarbyl, —O-halocarbyl, acyl, —O-acyl,—NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, or halogens, or(ii) two or more of R₄, R₅, R₆, R₇ and R₈ together form a ring, or (iii)at least three of R₄, R₅, R₆, R₇ and R₈ independently represent OH,hydrocarbyl, —O-hydrocarbyl, halocarbyl, —O-halocarbyl, —O-acyl,—NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen.4. A compound of Formula I or Formula II

wherein A is —CR₁₀R₁₁, —S(═O)₂—, —NR₁₂—, or C═O, wherein R₁₀ and R₁₁independently represent —H, —OH, hydrocarbyl, —CN, NO₂, or halogen, R₁₂is —H or hydrocarbyl; B is —(CR₁₃R₁₄)₁₋₃, C═O, CR₁₅R₁₆C═O, —S(═O)₂—,—NR₁₇— or —NR₁₈—C(═O)—, wherein each of R₁₃, R₁₄, R₁₅ and R₁₆independently represents —H, —OH, hydrocarbyl, —CN, —NO₂, or halogen,R₁₇ and R₁₈ independently represent H or hydrocarbyl; R₁ is —OH,O-hydrocarbyl, O-heterohydrocarbyl, —SO₂-hydrocarbyl, —CH═CH₂, halogen,—OSO₂NR₁₉R₂₀, —C(═O)—NR₂₁R₂₂, —NR₂₃—C(═O)H or —NR₃₅R₃₆ wherein each ofR₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₃₅ and R₃₆ independently represent —H orhydrocarbyl; R₂ is —H, —O-hydrocarbyl, —S-hydrocarbyl, hydrocarbyl, —CN,—NO₂, or halogen, R₃ is

wherein each of R₄, R₅, R₆, R₇ and R₈ independently represent —H, —OH,hydrocarbyl, —O-hydrocarbyl, —COOH, an ester of —COOH, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen, R₉ is —H and or hydrocarbyl, andeach R₂₉ to R₃₃ independently represents —H or hydrocarbyl; and whereintwo or more of R₄, R₅, R₆, R₇, R₈ and R₉ may together form a ring;wherein when R₁ is OH and R₃ is of Formula D, (i) at least one of R₄,R₅, R₆, R₇ and R₈ independently represent halocarbyl, —O-halocarbyl,—O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, andhalogen, or (ii) two or more of R₄, R₅, R₆, R₇ and R₈ together form aring, or (iii) at least three of R₄, R₅, R₆, R₇ and R₈ independentlyrepresent —OH, hydrocarbyl, —O-hydrocarbyl, halocarbyl, —O-halocarbyl,—O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, —NO₂, orhalogen wherein h is an optional bond, wherein G is CR₂₄R₂₅, wherein R₂₄and R₂₅ independently represent —H, —OH, hydrocarbyl, —CN, —NO₂, orhalogen, or wherein when h is present G is CR₂₄, wherein R₂₄ is —H, —OH,hydrocarbyl, —CN, —NO₂, or halogen; n is 0, 1 or 2, each D independentlyrepresents —O, NR₂₆ or CR₂₇R₂₈, wherein each R₂₆ independentlyrepresents —H and or hydrocarbyl; and each R₂₇ and R₂₈ independentlyrepresents —H, —OH, hydrocarbyl, —CN, —NO₂, or halogen; or salts of thecompound.
 5. The compound of claim 4, wherein the compound is of FormulaI.
 6. The compound of claim 4, wherein A is CR₁₀R₁₁ or C═O, wherein R₁₀and R₁₁ independently represent —H, —OH, hydrocarbyl, —CN, —NO₂, orhalogen.
 7. The compound of claim 4, wherein A is —CR₁₀R₁₁ or C═O,wherein R₁₀ and R₁₁ independently represent —H, —OH, hydrocarbyl orhalogen.
 8. The compound of claim 4, wherein A is CH₂ or C═O.
 9. Thecompound of claim 4, wherein B is (CR₁₃R₁₄)₁₋₃, C═O, or —S(═O)₂—,wherein each of R₁₃ and R₁₄, independently represents —H, —OH,hydrocarbyl, —CN, —NO₂, or halogen.
 10. The compound of claim 4, whereinB is CR₁₃R₁₄, C═O, or —S(═O)₂—, wherein each of R₁₃ and R₁₄,independently represents —H, —OH, hydrocarbyl, —CN, —NO₂, and orhalogen.
 11. The compound of claim 4, wherein B is (CH₂)₁₋₃, C═O, or—S(═O)₂—.
 12. The compound of claim 4, wherein B is —CH₂, C═O, or—S(═O)₂—.
 13. The compound of claim 4, wherein R₁ is —OH,O-heterohydrocarbyl, or —OSO₂NR₁₉R₂₀, wherein each of R₁₉ and R₂₀independently represents —H or hydrocarbyl.
 14. The compound of claim13, wherein at least one of R₁₉ and R₂₀ is H.
 15. The compound of claim13, wherein R₁₉ and R₂₀ are H.
 16. The compound of claim 13, wherein R₁is O-heterohydrocarbyl, wherein the O-heterohydrocarbyl is an O-acylgroup.
 17. The compound of claim 13, wherein R₁ is O-heterohydrocarbyl,wherein the O-heterohydrocarbyl group is an O-acetyl group.
 18. Thecompound of claim 13, wherein R₁ is O-heterohydrocarbyl, wherein theO-heterohydrocarbyl group is an alkoxy benzyl group.
 19. The compoundaccording to claim 18 wherein the alkoxy benzyl group is a C₁₋₆ alkoxybenzyl group.
 20. The compound according to claim 18 wherein the alkoxybenzyl group is a methoxy benzyl group.
 21. The compound according toclaim 18 wherein the alkoxy benzyl group is a 2-methoxy benzyl group ora 3-methoxy benzyl group.
 22. The compound of claim 4, wherein R₁ is—OH, O-acetyl group, —OSO₂NH₂, or a methoxy benzyl group.
 23. Thecompound of claim 4, wherein R₂ is an —O-hydrocarbyl group.
 24. Thecompound of claim 23, wherein R₂ is a —C₁₋₆ alkoxy groups.
 25. Thecompound of claim 23, wherein R₂ is methoxy.
 26. The compound of claim4, wherein R₃ is a group of Formula A

wherein each of R₄, R₅, R₆, R₇ and R₈ independently represents —H, —OH,hydrocarbyl, —O-hydrocarbyl, —COOH, an ester of —COOH, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen, wherein each R₂₉ to R₃₃independently represents —H or hydrocarbyl; and wherein two or more ofR₄, R₅, R₆, R₇, R₈ and R₉ may together form a ring.
 27. The compound ofclaim 4, wherein R₃ is a group of Formula B

wherein each of R₄, R₅, R₆, and R₇ independently represents —H, —OH,hydrocarbyl, —O-hydrocarbyl, —COOH, an ester of —COOH, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen, R₉ is —H or hydrocarbyl, and eachR₂₉ to R₃₃ independently represents —H or hydrocarbyl; and wherein twoor more of R₄, R₅, R₆, R₇, and R₉ may together form a ring.
 28. Thecompound of claim 4, wherein R₃ is a group of Formula C

wherein each of R₄, R₅, R₆, and R₈ independently represents —H, —OH,hydrocarbyl, —O-hydrocarbyl, —COOH, an ester of —COOH, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen, R₉ is H or hydrocarbyl, and each R₂₉to R₃₃ independently represents H or hydrocarbyl; and wherein two ormore of R₄, R₅, R₆, R₈, and R₉ may together form a ring.
 29. Thecompound of claim 4, wherein R₃ is a group of Formula D

wherein each of R₄, R₅, R₇, and R₈ independently represents —H, —OH,hydrocarbyl, —O-hydrocarbyl, —COOH, an ester of —COOH, halocarbyl,—O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen, R₉ is —H or hydrocarbyl, and eachR₂₉ to R₃₃ independently represents —H or hydrocarbyl; and wherein twoor more of R₄, R₅, R₇, R₈, and R₉ may together form a ring.
 30. Thecompound of claim 4, wherein each of R₄, R₅, R₆, R₇ and R₈ independentlyrepresents H, —OH, C₁₋₆ alkyl, C₁₋₆ aryl, —O—C₁₋₆ alkyl, —O—C₁₋₆ aryl,—COOH, —C₁₋₆ alkyl ester of —COOH, C₁₋₆ halocarbyl, —O—C₁₋₆ halocarbyl,—O-acetyl, —NR₂₉-acetyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN,—NO₂, or halogen, wherein each R₂₉ to R₃₃ independently represents —H orC₁₋₆ alkyl.
 31. The compound of claim 4, wherein each of R₄, R₅, R₆, R₇and R₈ independently represents H, —OH, C₁₋₆ alkyl, C₁₋₆ aryl, —O—C₁₋₆alkyl, —O—C₁₋₆ aryl, —COOH, —C₁₋₆ alkyl ester of —COOH, C₁₋₆ halocarbyl,—O—C₁₋₆ halocarbyl, —O-acetyl, —NH-acetyl, —O—SO₂NH₂, —NH₂, —NH—SO₂—NH₂,—CN, —NO₂, or halogen.
 32. The compound of claim 4, wherein each of R₄,R₅, R₆, R₇ and R₈ independently represents H, —OH, Me, Et, —OMe, —OEt,—OPh, —O-iPr , —COOMe, —CF₃, —OCF₃, F, Cl, —O-acetyl, —NH-acetyl,—O—SO₂NH₂, —NH₂, —NH—SO₂—NH₂, —CN, or —NO₂.
 33. The compound of claim 4,wherein R₄ is —H, —OH, —O-hydrocarbyl, —COOH, a salt of —COOH, or —CN.34. The compound of claim 4, wherein R₄ is —H, —OH, —OMe, —COOH or —CN.35. The compound of claim 4, wherein R₅ is —H, —OH, hydrocarbyl,—O-hydrocarbyl, halocarbyl, —O-halocarbyl, acyl, —O-acyl, —NR₂₉-acyl,—O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen.
 36. Thecompound of claim 4, wherein R₅ is —H, —OH, Me, Et, —OMe, —OEt, —OPh,—O-iPr , —CF₃, —OCF₃, F, Cl, —O-acetyl, —NH-acetyl, —O—SO₂NH₂, —NH₂,—NH—SO₂—NH₂, —CN, or —NO₂.
 37. The compound of claim 4, wherein R₆ is—H, —O-hydrocarbyl or —CN.
 38. The compound of claim 4, wherein R₆ is—H, —OMe, or —CN.
 39. The compound of claim 4, wherein R₇ is —H, or—O-hydrocarbyl.
 40. The compound of claim 4, wherein R₇ is —H or —OMe.41. The compound of claim 4, wherein R₉ is H.
 42. The compound of claim4, wherein R₉ is —H or C₁₋₆ alkyl.
 43. The compound of claim 4, whereineach R₂₉ to R₃₃ independently represents —H or C₁₋₆ alkyl.
 44. Thecompound of claim 4, wherein when R₁ is OH and R₃ is of Formula D, (i)at least one of R₄, R₅, R₆, R₇ and R₈ independently representshalocarbyl, —O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, or halogen.
 45. The compound of claim 4, wherein atleast one of R₄, R₅, R₆, R₇ and R₈ independently represents halocarbyl,—O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, and or halogen.
 46. The compound of claim 4, whereinwhen R₁ is OH and R₃ is of Formula D, (ii) two or more of R₄, R₅, R₆, R₇and R₈ together form a ring.
 47. The compound of claim 4, wherein two ormore of R₄, R₅, R₆, R₇ and R₈ together form a ring.
 48. The compound ofclaim 4, wherein when R₁ is OH and R₃ is of Formula D, (iii) at leastthree of R₄, R₅, R₆, R₇ and R₈ independently represent —OH, hydrocarbyl,—O-hydrocarbyl, halocarbyl, —O-halocarbyl, —O-acyl, —NR₂₉-acyl,—O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁, —NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen.
 49. Thecompound of claim 4, wherein at least three of R₄, R₅, R₆, R₇ and R₈independently represent OH, hydrocarbyl, —O-hydrocarbyl, halocarbyl,—O-halocarbyl, —O-acyl, —NR₂₉-acyl, —O—SO₂NR₁₉R₂₀, —NR₃₀R₃₁,—NR₃₂SO₂R₃₃, —CN, —NO₂, or halogen.
 50. The compound of claim 4, whereinh is not present.
 51. The compound of claim 4, wherein when h is notpresent G is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independently represent H orhydrocarbyl, and when h is present G is CR₂₄, wherein R₂₄ is H orhydrocarbyl.
 52. The compound of claim 4, wherein when h is not presentG is CR₂₄R₂₅, wherein R₂₄ and R₂₅ independently represent H or C₁₋₆alkyl, and when h is present G is CR₂₄, wherein R₂₄ is H or C₁₋₆ alkyl.53. The compound of claim 4, wherein when h is not present G is CR₂₄R₂₅,wherein R₂₄ and R₂₅ independently represent H, Et or Me, and when h ispresent G is CR₂₄, wherein R₂₄ is H or Me.
 54. The compound of claim 4,wherein when h is not present G is —CH₂—, —CHEt-, —CHMe- or —CMe₂-, andwhen h is present G is —CH— or —CMe-.
 55. The compound of claim 4,wherein n is
 1. 56. The compound of claim 4, wherein each Dindependently represents —CR₂₇R₂₈, wherein each R₂₇ and R₂₈independently represents —H, —OH, hydrocarbyl, —CN, —NO₂, or halogen.57. The compound of claim 4, wherein each D independently represents—CR₂₇R₂₈, wherein each R₂₇ and R₂₈ independently represents —H, OH, C₁₋₆alkoxy or C₁₋₆ alkyl.
 58. The compound of claim 4, wherein each Dindependently represents CHOH, CHOMe, CHOEt, or CH₂.
 59. The compound ofclaim 4, wherein —SO₂-hydrocarbyl is a —SO₂—C₁₋₆ alkyl group,
 60. Thecompound of claim 4, wherein —SO₂-hydrocarbyl is —SO₂-Me.
 61. Apharmaceutical composition comprising the compound of claim 4, and apharmaceutically acceptable carrier, diluent, excipient or adjuvant. 62.A medicament comprising the compound of claim.
 63. A method ofpreventing and/or inhibiting tumor growth comprising administering thecompound of claim 4 to a patient in need thereof.
 64. A compound whereinthe compound is:6-Benzyloxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;2-Benzyl-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3,5-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(4-methoxyphenethyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(2-(3,4-dimethoxyphenyl)-2-oxoethyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(2,3,4-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(2,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(2,3-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(2,5-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3-fluorobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Acetoxybenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyanobenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;2-(4-Cyanobenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-nitrobenzyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyanobenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-(trifluoromethoxy)benzyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;2-(2-Hydroxybenzyl)-7-methoxy-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(4-cyanobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3-hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-(Benzyloxy)-2-(3-ethoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-(Benzyloxy)-2-(3-isopropoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;3-((6-(Benzyloxy)-7-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)phenylacetate;2-(3-Aminobenzyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Acetamidobenzyl)-6-(benzyloxy)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-(Benzyloxy)-2-(3-methanesulfonylaminobenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3-(Methoxycarbonyl)benzyl)-6-triisopropylsilyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3-acetoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;2-Benzyl-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-2-(3,5-dimethoxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-phenoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-(triisopropylsilyloxy)benzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(4-methoxyphenethyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(pyridin-3-ylmethyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(pyridin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-acetamidobenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-acetoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-methanesulfonylaminobenzyl)-1,2,3,4-tetrahydroisoquinoline;2-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(2,5-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(2,3-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(2,3,4-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(2,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Fluorobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Isopropoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-acetylbenzyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Ethoxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyanobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(4-Cyanobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-nitrobenzyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Chlorobenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-trifluoromethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;2-(2-Hydroxybenzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydroisoquinolin-6-ol;2-(3-(Methoxycarbonyl)benzyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6,7-Dimethoxy-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-6-O-acetyl-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-6-O-methanesulfonyl-2-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(4-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-Benzyl-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2-methoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3,5-Dimethoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-methylbenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-phenoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-(O-sulfamoyl)benzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Ethoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(pyridin-3-ylmethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Acetylbenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(4-methoxyphenethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline7-Methoxy-2-(pyridin-2-ylmethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline2-(3-Acetamidobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(pyridin-4-ylmethyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Acetoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-(methylsulfonamido)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-ylsulfamate;2-(2-(3,4-Dimethoxyphenyl)-2-oxoethyl)-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3,4,5-trimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2,3-dimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3,4-dimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2,3,4-trimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2,5-dimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2,4,5-trimethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-(triisopropylsilyloxy)benzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Hydroxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyanobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(4-Cyanobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-nitrobenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Chlorobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-trifluoromethoxybenzyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Fluorobenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-Isopropoxybenzyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3-(Methoxycarbonyl)benzyl)-6-O-sulfamoyl-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(4-methoxybenzoyl)-6-benzyloxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyanobenzoyl)-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(4-Cyanobenzoyl)-6-benzyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3,5-Dimethoxybenzoyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(2-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(4-methoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;2-(3,4-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline:2-(3,5-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;2-(3,5-Dimethoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2-methoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-methoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(4-methoxybenzoyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;2-(3,4-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamate-1,2,3,4-tetrahydroisoquinoline;2-(3,5-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-methoxy-6-O-sulfamoyl-2-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(4-methoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one;6-(Benzyloxy)-2-(3,5-dimethoxybenzoyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one;6-Benzyloxy-7-methoxy-2-(2-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one;6-Benzyloxy-7-methoxy-2-(3-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one;6-Benzyloxy-2-(3,5-dimethoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one;6-(Benzyloxy)-7-methoxy-2-(3,4-dimethoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one;6-Benzyloxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Benzyloxy-2-(3-cyanobenzoyl)-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one;6-(Benzyloxyl)-2-(4-cyanobenzoyl)-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one;2-(3,5-Dimethoxybenzoyl)-6-hydroxy-3,4-dihydro-2H-isoquinoline-1-one;6-Hydroxy-7-methoxy-2-(2-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one;6-Hydroxy-7-methoxy-2-(3-methoxybenzoyl)-3,4-dihydro-2H-isoquinoline-1-one;6-Hydroxy-7-methoxy-2-(4-methoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(3,5-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one;2-(3,4-Dimethoxybenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one;6-Hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(3-Cyanobenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one;2-(4-Cyanobenzoyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinoline-1-one;2-(3,5-Dimethoxybenzoyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline-1-one;2-(4-Methoxybenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;7-Methoxy-2-(2-methoxybenzoyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;7-Methoxy-2-(3-methoxybenzoyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;2-(3,5-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;2-(3,4-Dimethoxybenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;7-methoxy-6-O-sulfamoyl-2-(3,4,5-trimethoxybenzoyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(3-Cyanobenzoyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline-1-one;7-Methoxy-2-(4-methoxybenzyl)-6-(triisopropylsilyloxy)-3,4-dihydro-2H-isoquinolin-1-one;7-Methoxy-2-(3-methoxybenzyl)-6-(3-methoxybenzyloxy)-3,4-dihydro-2H-isoquinolin-1-one;7-Methoxy-2-(2-methoxybenzyl)-6-(2-methoxybenzyloxy)-3,4-dihydro-2H-isoquinolin-1-one;6-(Benzyloxy)-2-(3,4,5-dimethoxybenzyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one;6-(benzyloxy)-7-methoxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(benzyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-ones;6-Hydroxy-7-methoxy-2-(4-methoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one;6-Hydroxy-7-methoxy-2-(3-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Hydroxy-7-methoxy-2-(2-methoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(3,5-dimethoxybenzyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one;6-hydroxy-7-methoxy-2-(3,4,5-trimethoxybenzyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(benzyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-ones;7-Methoxy-2-(4-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline;7-Methoxy-2-(2-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline;7-Methoxy-2-(3-methoxybenzyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinoline;2-(3,5-Dimethoxybenzyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;7-methoxy-6-O-sulfamoyl-2-(3,4,5-trimethoxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one;6-Benzyloxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-trifluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(toluene-3-sulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-2-(3-chloro-benzenesulfonyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyano-benzenesulfonyl)-6-triisopropylsilyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(2-Cyano-benzenesulfonyl)-6-triisopropylsilyloxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2-methoxy-benzenesulfonyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(4-methoxy-benzenesulfonyl)-6-triisopropylsilyloxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2-(methoxycarbonyl)benzenesulfonyl)-6-benzyloxy-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-trifluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(toluene-3-sulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Chloro-benzenesulfonyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;2-(2-Cyano-benzenesulfonyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline,6-Hydroxy-7-methoxy-2-(2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;6-Hydroxy-7-methoxy-2-(4-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyano-benzenesulfonyl)-6-hydroxy-7-methoxy-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2-(methoxycarbonyl)benzenesulfonyl)-6-hydroxy-1,2,3,4-tetrahydroisoquinoline;2-(3-Cyano-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(3-methoxy-benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-6-O-sulfamoyl-2-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;2-(3-Chloro-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-6-O-sulfamoyl-2-(toluene-3-sulfonyl)-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-6-O-sulfamoyl-2-(3-trifluoromethoxy-benzenesulfonyl)-1,2,3,4-tetrahydroisoquinoline;2-(2-Cyano-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2-methoxy-benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(4-methoxy-benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;7-Methoxy-2-(2-(methoxycarbonyl)benzenesulfonyl)-6-O-sulfamoyl-1,2,3,4-tetrahydroisoquinoline;6-Benzyloxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Benzyloxy-7-methoxy-2-(2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Benzyloxy-7-methoxy-2-(4-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Benzyloxy-2-(3-chloro-benzenesulfonyl)-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one;6-Benzyloxy-7-methoxy-2-(3-carboxymethyl-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Hydroxy-7-methoxy-2-(2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Hydroxy-7-methoxy-2-(3-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;6-Hydroxy-7-methoxy-2-(4-methoxy-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(3-Chloro-benzenesulfonyl)-6-hydroxy-7-methoxy-3,4-dihydro-2H-isoquinolin-1-one;6-Hydroxy-7-methoxy-2-(3-carboxymethyl-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;7-Methoxy-2-(2-methoxy-benzenesulfonyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;7-Methoxy-2-(3-methoxy-benzenesulfonyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;7-Methoxy-2-(4-methoxy-benzenesulfonyl)-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;2-(3-Chloro-benzenesulfonyl)-7-methoxy-6-O-sulfamoyl-3,4-dihydro-2H-isoquinolin-1-one;6-O-Sulfamoyl-7-methoxy-2-(3-carboxymethyl-benzenesulfonyl)-3,4-dihydro-2H-isoquinolin-1-one;2-(Benzyloxy)-1-methoxy-4-((E)-2-nitroprop-1-enyl)benzene;2-(Benzyloxy)-1-methoxy-4-(2-nitropropyl)benzene;1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-amine;N-(1-(3-(Benzyloxy)-4-methoxyphenyl)propan-2-yl)acetamide;1-(6-(Benzyloxy)-3,4-dihydro-7-methoxy-3-methylisoquinolin-2(1H)-yl)ethanone;6-(Benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinoline;2-(3-Methoxybenzyl)-6-(benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinoline;2-(3,5-Dimethoxybenzyl)-6-(benzyloxy)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinoline;2-(3,4,5-Trimethoxybenzyl)-6-(benzyloxy)-1,2,3-tetrahydro-7-methoxy-3-methylisoquinoline;2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-ol;2-(3,5-Dimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-ol;2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-ol;2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-O-sulfamate;2-(3,5-dimethoxy-benzyl)-7-methoxy-3-methyl-1,2,3,4-tetrahydro-isoquinolin-6-O-sulfmate;2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3-methylisoquinolin-6-O-sulfamate;3,4-Dihydro-7-methoxy-3,3-dimethylisoquinolin-6-ol;1,2,3,4-Tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ol;7-Methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-1,2,3,4-tetrahydro-isoquinoline;7-Methoxy-2-(3-methoxy-benzyl)-3,3-dimethyl-6-triisopropylsilanyloxy-1,2,3,4-tetrahydro-isoquinoline;7-Methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-2-(3,4,5-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinoline;2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ol;7-Methoxy-3,3-dimethyl-2-(3,4,5-trimethoxy-benzyl)-1,2,3,4-tetrahydro-isoquinolin-6-ol;2-(3-Methoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ylsulfamate;2-(3,4,5-Trimethoxybenzyl)-1,2,3,4-tetrahydro-7-methoxy-3,3-dimethylisoquinolin-6-ylsulfamate;(7-Methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-3,4-dihydro-1H-isoquinolin-2-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(3,5-Dimethoxy-phenyl)-(7-methoxy-3,3-dimethyl-6-triisopropylsilanyloxy-3,4-dihydro-1H-isoquinolin-2-yl)-methanone;(6-Hydroxy-7-methoxy-3,3-dimethyl-3,4-dihydro-1H-isoquinolin-2-yl)-(3,4,5-trimethoxy-phenyl)-methanone;(3,4-Dihydro-6-hydroxy-7-methoxy-3,3-dimethylisoquinolin-41H)-yl)(3,5-dimethoxyphenyl)methanone;Sulfamic acid7-methoxy-3,3-dimethyl-2-(3,4,5-trimethoxy-benzoyl)-1,2,3,4-tetrahydro-isoquinolin-6-ylester; or Sulfamic acid2-(3,5-dimethoxy-benzoyl)-7-methoxy-3,3-dimethyl-1,2,3,4-tetrahydro-isoquinolin-6-ylester.
 65. A pharmaceutically active composition comprising the compoundof claim
 64. 66. A method of preventing and/or inhibiting tumor growthcomprising administering to a patient in need thereof a compositioncomprising a pharmaceutically active amount of the compound of claim 64.67. A method of inhibiting tumor growth comprising administering to apatient in need thereof a composition comprising a pharmaceuticallyactive amount of the compound of claim 64.